Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Before the introduction of insulin, there were few reported cases of pregnancy complicated by diabetes because women with the disease too often did not live to childbearing age, and when they did, they were often counseled to terminate their pregnancies. Perinatal and maternal mortality in the limited number of reported pregnancies were 70% and 40%, respectively,¹ making the risks of continuing the pregnancy quite high.

After insulin became available, maternal mortality dropped dramatically, down to a few percent. Perinatal mortality also declined, but it took several decades to achieve a similar magnitude of reduction.² Today, with insulin therapy and tight glucose control as well as improved perinatal care, almost all women with diabetes can contemplate pregnancy with greater hope for normal outcomes.

Problems persist, however. Maternal diabetes continues to cause a variety of adverse outcomes, including infants large for gestational age, prematurity, and structural birth defects. Birth defects and prematurity, in fact, are the top causes of the unacceptably high infant mortality rate in the United States – a rate that is about 70% higher than the average in comparable developed countries.³

Infant mortality is considered an indicator of population health and of the development of a country; to reduce its rate, we must address these two areas.

Women with type 1 and type 2 diabetes are five times more likely to have a child with birth defects than are nondiabetic women.⁴ Up to 10% of women with preexisting diabetes will have fetuses with a major congenital malformation.⁵

Over the years we have been striving in our Center for Birth Defects Research to understand the pathomechanisms and the molecular and epigenetic alterations behind the high rates of birth defects in the offspring of women with preexisting diabetes. We have focused on heart defects and neural tube defects (particularly the latter), which together cause significant mortality, morbidity, disability, and human suffering.

Using animal models that mimic human diabetic pregnancy, we have made significant strides in our understanding of the mechanisms, uncovering molecular pathways involving oxidative stress, senescence/premature cellular aging, and epigenetic modifications (Figure 1). Understanding these pathways is providing us, in turn, with potential therapeutic targets and approaches that may be used in the future to prevent birth defects in women who enter pregnancy with type 1 or type 2 diabetes.

Unraveling the role of oxidative stress

Our mouse models accurately reflect the human conditions of diabetes in pregnancy and diabetic embryopathy. Offspring of mice with type 1 and type 2 diabetes have a similarly higher rate of neural tube defects and congenital heart disease, compared to mice without diabetes. We observe a similar incidence of anencephaly and spina bifida, and of cardiac septation defects in the mouse embryo hearts, for instance.

A primary mechanism and causal event of diabetic embryopathy is hyperglycemia-induced apoptosis in embryonic cells. Excessive cell death in the neural epithelium or in the developing heart leads to abnormal organogenesis and dysfunctional developmental events that cause birth defects. We have identified pathways leading to apoptosis, and have found that many of these pathways crosstalk with each other.

Hyperglycemia induces oxidative stress – one of these pathways – by causing sustained generation of reactive oxygen species. The cells’ mitochondrial function is significantly impaired by the hyperglycemia response, and this diabetes-induced mitochondrial dysfunction further increases the production of reactive oxygen species and a weakening of the endogenous cellular antioxidant systems, both of which then exacerbate oxidative stress.

Our research has detailed what happens downstream. We’ve learned that oxidative stress in embryos exposed to maternal diabetes activates a cascade of proapoptotic kinase signaling molecules – for example, protein kinase C isoforms such as PKCalpha; apoptosis signal-regulating kinase 1; and c-Jun-N-terminal kinases – that ultimately lead to abnormal cell death in the neuroepithelium before neural tube closure (Figure 2).⁵

Hyperglycemia also alters membrane biochemistry in the developing embryo, suppressing lipids including arachidonic acid and myoinositol, and induces the elevation of other molecules that cause newly synthesized proteins to be misfolded. A build-up of misfolded/unfolded proteins triggers or exacerbates endoplasmic reticulum stress, which, like oxidative stress, plays a role in the activation of proapoptotic kinase signaling and apoptosis.⁶

When we’ve deleted genes for some of the proapoptotic kinase–signaling intermediates, or otherwise inhibited oxidative and endoplasmic reticulum stresses, we’ve been able to ameliorate neural cell apoptosis and the formation of neural tube defects. Studying the processes both forward and backward gives us confidence that the pathways are real and important, and that altering the pathways can alter the outcomes.

 

Reduced autophagy and induction of cellular senescence

Just as mitochondria are negatively affected by hyperglycemic conditions, so are autophagosomes – organelles that play a key role in removing abnormal or damaged stem cells and cellular components (including unfolded protein aggregates) and in maintaining cellular homeostasis. A high level of autophagy is essential for neural tube closure as well as cardiac morphogenesis.

In our models, maternal diabetes significantly suppressed the process of autophagy in neuroepithelial cells. We have identified responsible molecular intermediates and a key regulating gene for autophagy impairment and have found that deletion of the gene restores autophagy and reduces the development of neural tube defects.⁴ Administration of a naturally occurring compound, trehalose, which reactivates autophagy, had a similar effect.⁷Exposure to hyperglycemia not only causes cell death and suppresses autophagy, it also impairs other aspects of cellular function. More recently, we have shown that cells in the neuroepithelium become quiescent and cease proliferating. The quiescent cells, those cells with premature aging markers, also produce cytokines that influence the functioning and development of neighboring cells, causing additional cell death.

All told, premature senescence in the neuroepithelium adversely affects the neurulation process, leading to neural tube defects. In our mouse model, the senomorphic agent rapamycin suppressed cellular senescence, reduced the number of apoptotic neuroepithelial cells, and reduced the formation of neural tube defects.⁸

The role of epigenetics, future interventions

Epigenetics – the process by which gene expression and function can be modified by environmental conditions without modification of the DNA sequence – has become an additional area of focus in diabetic embryopathy. Our lab has studied the overexpression of both DNA methyltransferases (DNMTs) that cause DNA hypermethylation, and of microRNAs (miRNAs) that can suppress gene expression at the posttranscriptional level. Both are considered to be primary epigenetic mechanisms involved in human diseases and it appears that they are influential in the incidence of birth defects in diabetic mothers.

In our mouse models, maternal diabetes induces DNA hypermethylation via the increase of DNMTs, leading to the silencing of genes essential for neural tube closure and formation of the developing heart. MiRNAs also play a role; in addition to finding altered DNMT activity in the neural epithelium and other tissues of diabetes-exposed embryos, we also found altered miRNA expression. By deleting miRNA genes or by inhibiting DNMT activity through treatment with antioxidants, we saw significant reductions in birth defects.

In one study of the green tea polyphenol epigallocatechin gallate (EGCG), we demonstrated inhibition of diabetes-elevated DNMT expression and activity and suppression of DNA hypermethylation. The expression of genes essential for neural tube closure was restored, with a subsequent reduction in neural tube defects from 29.5% to 2% in embryos treated with EGCG.⁹

Our interventions to reverse or alter the mechanisms and pathways leading to birth defects have not only helped prove causation, but have given us hope for the future. Antioxidants are among the compounds that could be used as dietary supplements during pregnancy to prevent structural birth defects (Figure 3). Other compounds could activate the process of autophagy (for example, trehalose) and antisenescence compounds similar to rapamycin could be used to reduce numbers of senescent cells in the neuroepithelium or the developing heart.

Dr. Reece and Dr. Yang reported no relevant disclosures.

Dr. Reece, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president, endowed professor and director of CARTI, and codirector of the Center for Birth Defects.
Dr. Yang is professor of obstetrics, gynecology, and reproductive sciences and director, Center for the Study of Birth Defects at the University of Maryland School of Medicine, both in Baltimore.

*This story was updated on Nov. 3, 2022

References

1. Z Zhiyong and Reece EA. Clin Lab Med. 2013;33(2)207-33.

2. Reece EA and Coustan DR. Diabetes and obesity in women. Wolters Kluwer: 2019. 4th ed. (https://www.amazon.com/Diabetes-Obesity-Women-Albert-Reece/dp/1496390547).

3. The Peterson-KFF Health System Tracker. www.healthsystemtracker.org.

4. Wang F et al. Nat. Commun. 2017;8:15182.

5. Yang P et al. Am J Obstet Gynecol. 2015;212(5):569-79.

6. Li X et al. Diabetes. 2013 Feb;62(2):599-608.

7. Xu C et al. Am J Physiol Endocrinol Metab. 2013 Sep 1;305(5):E667-78.

8. Xu C et al. Sci Adv. 2021;7(27):eabf5089.

9. Zhong J et al. Am J Obstet Gynecol. 2016 Sep;215(3):368.e1-10.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

Many issues surrounding pregnancy care of women with preexisting diabetes remain challenging, especially in light of the relentless increase in maternal morbidity and mortality in the United States and globally. Rising rates of death and severe morbidity in diabetic women have continued despite significant advances in insulin pharmacology and administration technology.

However, despite these advances in glucose monitoring and insulin administration, fetal mortality and childhood morbidity rates continue to climb. This is because critical fetal structural anomalies arise from developmental errors occurring in the embryonic period – between 2 and 13 weeks of gestation – a time when most women with preexisting diabetes are just entering into prenatal care, often with suboptimal glycemic control.

Thus, significant future progress in reducing fetal mortality and childhood disability in infants of diabetic mothers will depend upon effective interventions in the first trimester while embryogenesis and critical organ formation are underway.

Dr. Moore is professor emeritus of maternal-fetal medicine and chair emeritus in the department of obstetrics, gynecology, and reproductive sciences at UC San Diego Health. He reported no disclosures.

*This story was updated on Nov. 3, 2022.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.

DENVER – One expert’s clinical experience suggests that Ellacor, a dermal microcoring device that became available in the United States in October 2022, is an effective treatment for facial wrinkles and tightening.

“It’s early yet, but I have treated dozens of patients with this device, and they have been happy with the results,” Mathew M. Avram, MD, JD, said at the annual meeting of the American Society for Dermatologic Surgery. “This is a new technique that offers the ability to remove a significant amount of damaged, lax skin without concern for scarring,” he said.

A brainchild of dermatologists and plastic surgeons at Massachusetts General Hospital, Boston, the first-in-class device is cleared by the Food and Drug Administration for the treatment of moderate and severe wrinkles in the mid and lower face in adults aged 22 years or older with Fitzpatrick skin types I-IV. It features a proprietary needle design that makes a series of high throughput microexcisions in epidermal and dermal tissue, with minimal downtime and without using thermal energy.

“It doesn’t do anything equivalent to a facelift, but the concept is a facelift by thousands of micro-punch excisions,” said Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital. “Rather than pulling up the skin and lifting it and cutting the excess skin like we do with a facelift, we are creating thousands of smaller-scale tissue removals with immediate closures to do the same thing. The micro-cores are about the size of a 22-gauge needle and there is no scarring due to the small size of these tissue extractions.”

The device features needle cartridges capable of excising up to 24,000 cores per treatment. According to data from Cytrellis, the manufacturer, the equivalent of about 2 inches of skin can be removed during the procedure, which typically takes fewer than 30 minutes to perform. “There is no heat whatsoever,” Dr. Avram said. “In my experience, it especially helps with jawline definition, the lower medial cheek excess skin, and accordion lines in that area.”

In a pivotal trial of the device, 51 patients with mid to lower face wrinkles (moderately deep or deep wrinkles with well-defined edges) were treated 2-3 times with 7%-8% skin removal and up to a 5-mm needle coring depth). The investigators found that 40% of study participants achieved an improvement of 2 grades on the Lemperle Wrinkle Severity Scale and that the rate of overall satisfaction (slightly, somewhat, and extremely satisfied) was 86%.

In addition, 90% showed improvement of treated sites on the Global Aesthetic Improvement Scale, and 70% were comfortable enough to go out in public or return to work 3 days after treatment. Common side effects that can occur immediately post treatment include redness, swelling, and pinpoint bleeding, which typically clear in a few days.

Dr. Avram, immediate past president of the ASDS, has posted videos to his Instagram feed that show him treating patients with the Ellacor device and he admits that the procedure looks painful. “There are all these tear emojis and people cursing me out,” he said, referring to responses from his Instagram followers.

Proper local anesthesia prior to treatment is key. “I perform nerve blocks and infiltrate the skin,” he said. “You have to cover the whole treatment area. If you don’t, then it’s going to hurt. The average pain score is 1.9 out of 10. The highest pain score I’ve gotten from a patient is a 3 out of 10.”

Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton, and has ownership and/or shareholder interest in Cytrellis.

Doctor, doctor, gimme the news. I got a bad case of misidentifying you

There are a lot of medical specialties out there. A lot. Everything from allergists to urologists, with something like 150 subspecialties grouped in among the larger specialties. Can you name every one? Do you know what they do?

The point is, telling a patient or anyone in the general public that you’re an ophthalmologist may not be as helpful as you might think, if a recent study is to be believed. In a survey of 204 adults, conducted at the Minnesota State Fair of all places, researchers asked volunteers to define 14 different specialties, as well as five medical seniority titles.

Minerva Studio/ThinkStock

The results were less than stellar. While more than 90% of people correctly defined what cardiologists and dermatologists do, 6 of the other 12 specialists were correctly identified by less than half of those surveyed. Nephrology was at the bottom, correctly identified by just 20% of the fair-attending public, followed by internists (21%), intensivists (29%), hospitalists (31%), pulmonologists (43%), and neonatologists at 48%. The hospitalists are particularly concerning. They’re doctors, but in hospitals. How hard is that? (Yes, it’s obviously more complicated than that, but still.)

The general public didn’t fare much better when it came to correctly lining up the order of progression from medical student to attending. Just 12% managed to place all five in the correct order of med student, intern, senior resident, fellow, then attending, with senior resident proving especially troublesome. More than 40% put senior resident at the end, compared with 27% for attending. Which does make a certain amount of sense, since it has senior in the name.

While the results speak for themselves – maybe elaborate on what the heck your fancy title actually means – it’s too bad the researchers didn’t throw in something really tricky. If two-thirds of the population can’t identify a hospitalist, just imagine how many people would misidentify an otolaryngologist.
 

Beach-to-table sand could fight obesity

People are always looking for the new weight loss solution. Whether it’s to just look good in a new pair of jeans or reduce the risk of cardiovascular disease, there are millions of diets and exercise routines out here. We’re here to tell you that the next new therapy to reduce fat comes from a very unsuspecting place: Sand.

David Stanley

Like sand from the beach and desert, sand? Well, yes and no.

The research involved engineered porous silica particles made from sand that are designed to have a high surface area. Investigators used a two-step GI model in which gastric digestion was modeled for 30 minutes, followed by a 60-minute intestinal phase, to show that the porous silica particles helped prevent fat and sugar adsorption within the GI tract.

By mimicking the gastrointestinal environment during digestion of a high-fat, high-carb meal, the researchers found that the porous silica created an “anti-obesity effect” by restricting the adsorption of those fats and carbohydrates.

Okay, but how is that on the tummy? Much gentler on the stomach than a drug such as orlistat, said senior researcher Paul Joyce, PhD, of the University of South Australia, Adelaide, who noted the lack of effective therapies without side effects, such as bloating, diarrhea, and abdominal pain, that deter people from treatment.

Obesity affects over 1.9 billion people worldwide, so the researchers think this could be a breakthrough. Reducing obesity may be one of the most preventable ways to reduce the risk of type 2 diabetes, heart disease, and other weight-related chronic conditions. A treatment solution this simple could be the answer to this global health crisis.

Who would have thought the solution would be as simple as sand? But how would the sand get in our stomachs? Do we sprinkle it on our food? Mix it in during cooking? Or will the sand come in pill form? We sure hope it’s that third one.
 

I am Reliebo. I am here to help you

Halloween is almost here, and the LOTME staff has been trying to make the office look as scary as possible: Headless vampires, ghost clowns, Ted Cruz, gray tombstones, pink hearts, green clovers, red balloons. Wait a second, those last three are Lucky Charms marshmallows, aren’t they? We’ll use those some other time.

University of Tsukuba

What are we not using to decorate? Well, besides marshmallows from cereal, we’re not using Reliebo. That’s what we’re not using. Reliebo is a cute little fuzzy robot, and is not at all scary. Reliebo was designed to be the opposite of scary. Reliebo “may reduce fear as well as alleviate the perception of pain during medical treatments, including vaccinations,” senior author Fumihide Tanaka, PhD, of the University of Tsukuba (Japan) said in a written statement.

The soft, fur-covered robot contains small airbags that can inflate in response to hand movements. When study participants were subjected to a moderate heat stimulus on one arm, those who held the robot with the other arm experienced less pain than those who did not have a Reliebo.

The results also were encouraging when Dr. Tanaka and associates measured the levels of oxytocin and cortisol (biomarkers for stress) from the subjects’ saliva samples and evaluated their fear of injections and their psychological state before and after the experiments.

After looking at that photo of Reliebo for a while, though, we have to admit that we’re having a bit of a rethink about its cuteness. Is it cute, or weird-looking? An office full of fuzzy little inflating robots just could be seriously creepy. Please don’t tell the rest of the staff about this. We want to surprise them on Monday.

Doctor, doctor, gimme the news. I got a bad case of misidentifying you

There are a lot of medical specialties out there. A lot. Everything from allergists to urologists, with something like 150 subspecialties grouped in among the larger specialties. Can you name every one? Do you know what they do?

The point is, telling a patient or anyone in the general public that you’re an ophthalmologist may not be as helpful as you might think, if a recent study is to be believed. In a survey of 204 adults, conducted at the Minnesota State Fair of all places, researchers asked volunteers to define 14 different specialties, as well as five medical seniority titles.

Minerva Studio/ThinkStock

The results were less than stellar. While more than 90% of people correctly defined what cardiologists and dermatologists do, 6 of the other 12 specialists were correctly identified by less than half of those surveyed. Nephrology was at the bottom, correctly identified by just 20% of the fair-attending public, followed by internists (21%), intensivists (29%), hospitalists (31%), pulmonologists (43%), and neonatologists at 48%. The hospitalists are particularly concerning. They’re doctors, but in hospitals. How hard is that? (Yes, it’s obviously more complicated than that, but still.)

The general public didn’t fare much better when it came to correctly lining up the order of progression from medical student to attending. Just 12% managed to place all five in the correct order of med student, intern, senior resident, fellow, then attending, with senior resident proving especially troublesome. More than 40% put senior resident at the end, compared with 27% for attending. Which does make a certain amount of sense, since it has senior in the name.

While the results speak for themselves – maybe elaborate on what the heck your fancy title actually means – it’s too bad the researchers didn’t throw in something really tricky. If two-thirds of the population can’t identify a hospitalist, just imagine how many people would misidentify an otolaryngologist.
 

Beach-to-table sand could fight obesity

People are always looking for the new weight loss solution. Whether it’s to just look good in a new pair of jeans or reduce the risk of cardiovascular disease, there are millions of diets and exercise routines out here. We’re here to tell you that the next new therapy to reduce fat comes from a very unsuspecting place: Sand.

David Stanley

Like sand from the beach and desert, sand? Well, yes and no.

The research involved engineered porous silica particles made from sand that are designed to have a high surface area. Investigators used a two-step GI model in which gastric digestion was modeled for 30 minutes, followed by a 60-minute intestinal phase, to show that the porous silica particles helped prevent fat and sugar adsorption within the GI tract.

By mimicking the gastrointestinal environment during digestion of a high-fat, high-carb meal, the researchers found that the porous silica created an “anti-obesity effect” by restricting the adsorption of those fats and carbohydrates.

Okay, but how is that on the tummy? Much gentler on the stomach than a drug such as orlistat, said senior researcher Paul Joyce, PhD, of the University of South Australia, Adelaide, who noted the lack of effective therapies without side effects, such as bloating, diarrhea, and abdominal pain, that deter people from treatment.

Obesity affects over 1.9 billion people worldwide, so the researchers think this could be a breakthrough. Reducing obesity may be one of the most preventable ways to reduce the risk of type 2 diabetes, heart disease, and other weight-related chronic conditions. A treatment solution this simple could be the answer to this global health crisis.

Who would have thought the solution would be as simple as sand? But how would the sand get in our stomachs? Do we sprinkle it on our food? Mix it in during cooking? Or will the sand come in pill form? We sure hope it’s that third one.
 

I am Reliebo. I am here to help you

Halloween is almost here, and the LOTME staff has been trying to make the office look as scary as possible: Headless vampires, ghost clowns, Ted Cruz, gray tombstones, pink hearts, green clovers, red balloons. Wait a second, those last three are Lucky Charms marshmallows, aren’t they? We’ll use those some other time.

University of Tsukuba

What are we not using to decorate? Well, besides marshmallows from cereal, we’re not using Reliebo. That’s what we’re not using. Reliebo is a cute little fuzzy robot, and is not at all scary. Reliebo was designed to be the opposite of scary. Reliebo “may reduce fear as well as alleviate the perception of pain during medical treatments, including vaccinations,” senior author Fumihide Tanaka, PhD, of the University of Tsukuba (Japan) said in a written statement.

The soft, fur-covered robot contains small airbags that can inflate in response to hand movements. When study participants were subjected to a moderate heat stimulus on one arm, those who held the robot with the other arm experienced less pain than those who did not have a Reliebo.

The results also were encouraging when Dr. Tanaka and associates measured the levels of oxytocin and cortisol (biomarkers for stress) from the subjects’ saliva samples and evaluated their fear of injections and their psychological state before and after the experiments.

After looking at that photo of Reliebo for a while, though, we have to admit that we’re having a bit of a rethink about its cuteness. Is it cute, or weird-looking? An office full of fuzzy little inflating robots just could be seriously creepy. Please don’t tell the rest of the staff about this. We want to surprise them on Monday.

Doctor, doctor, gimme the news. I got a bad case of misidentifying you

There are a lot of medical specialties out there. A lot. Everything from allergists to urologists, with something like 150 subspecialties grouped in among the larger specialties. Can you name every one? Do you know what they do?

The point is, telling a patient or anyone in the general public that you’re an ophthalmologist may not be as helpful as you might think, if a recent study is to be believed. In a survey of 204 adults, conducted at the Minnesota State Fair of all places, researchers asked volunteers to define 14 different specialties, as well as five medical seniority titles.

Minerva Studio/ThinkStock

The results were less than stellar. While more than 90% of people correctly defined what cardiologists and dermatologists do, 6 of the other 12 specialists were correctly identified by less than half of those surveyed. Nephrology was at the bottom, correctly identified by just 20% of the fair-attending public, followed by internists (21%), intensivists (29%), hospitalists (31%), pulmonologists (43%), and neonatologists at 48%. The hospitalists are particularly concerning. They’re doctors, but in hospitals. How hard is that? (Yes, it’s obviously more complicated than that, but still.)

The general public didn’t fare much better when it came to correctly lining up the order of progression from medical student to attending. Just 12% managed to place all five in the correct order of med student, intern, senior resident, fellow, then attending, with senior resident proving especially troublesome. More than 40% put senior resident at the end, compared with 27% for attending. Which does make a certain amount of sense, since it has senior in the name.

While the results speak for themselves – maybe elaborate on what the heck your fancy title actually means – it’s too bad the researchers didn’t throw in something really tricky. If two-thirds of the population can’t identify a hospitalist, just imagine how many people would misidentify an otolaryngologist.
 

Beach-to-table sand could fight obesity

People are always looking for the new weight loss solution. Whether it’s to just look good in a new pair of jeans or reduce the risk of cardiovascular disease, there are millions of diets and exercise routines out here. We’re here to tell you that the next new therapy to reduce fat comes from a very unsuspecting place: Sand.

David Stanley

Like sand from the beach and desert, sand? Well, yes and no.

The research involved engineered porous silica particles made from sand that are designed to have a high surface area. Investigators used a two-step GI model in which gastric digestion was modeled for 30 minutes, followed by a 60-minute intestinal phase, to show that the porous silica particles helped prevent fat and sugar adsorption within the GI tract.

By mimicking the gastrointestinal environment during digestion of a high-fat, high-carb meal, the researchers found that the porous silica created an “anti-obesity effect” by restricting the adsorption of those fats and carbohydrates.

Okay, but how is that on the tummy? Much gentler on the stomach than a drug such as orlistat, said senior researcher Paul Joyce, PhD, of the University of South Australia, Adelaide, who noted the lack of effective therapies without side effects, such as bloating, diarrhea, and abdominal pain, that deter people from treatment.

Obesity affects over 1.9 billion people worldwide, so the researchers think this could be a breakthrough. Reducing obesity may be one of the most preventable ways to reduce the risk of type 2 diabetes, heart disease, and other weight-related chronic conditions. A treatment solution this simple could be the answer to this global health crisis.

Who would have thought the solution would be as simple as sand? But how would the sand get in our stomachs? Do we sprinkle it on our food? Mix it in during cooking? Or will the sand come in pill form? We sure hope it’s that third one.
 

I am Reliebo. I am here to help you

Halloween is almost here, and the LOTME staff has been trying to make the office look as scary as possible: Headless vampires, ghost clowns, Ted Cruz, gray tombstones, pink hearts, green clovers, red balloons. Wait a second, those last three are Lucky Charms marshmallows, aren’t they? We’ll use those some other time.

University of Tsukuba

What are we not using to decorate? Well, besides marshmallows from cereal, we’re not using Reliebo. That’s what we’re not using. Reliebo is a cute little fuzzy robot, and is not at all scary. Reliebo was designed to be the opposite of scary. Reliebo “may reduce fear as well as alleviate the perception of pain during medical treatments, including vaccinations,” senior author Fumihide Tanaka, PhD, of the University of Tsukuba (Japan) said in a written statement.

The soft, fur-covered robot contains small airbags that can inflate in response to hand movements. When study participants were subjected to a moderate heat stimulus on one arm, those who held the robot with the other arm experienced less pain than those who did not have a Reliebo.

The results also were encouraging when Dr. Tanaka and associates measured the levels of oxytocin and cortisol (biomarkers for stress) from the subjects’ saliva samples and evaluated their fear of injections and their psychological state before and after the experiments.

After looking at that photo of Reliebo for a while, though, we have to admit that we’re having a bit of a rethink about its cuteness. Is it cute, or weird-looking? An office full of fuzzy little inflating robots just could be seriously creepy. Please don’t tell the rest of the staff about this. We want to surprise them on Monday.

When 32-year-old Brittany Dicks was diagnosed with stage II triple negative breast cancer in January 2022, she wasn’t worried about the cost of treatment. A medical assistant in Charleston, S.C., Ms. Dicks had full-time employment with health benefits.

But when she wasn’t able to work for several months because of chemotherapy and its side effects, Ms. Dicks lost her job. Her health insurance coverage ended in May. And although she filed for Medicaid at the beginning of June, it wasn’t approved until September.

Meanwhile, Ms. Dicks still needed treatment. She estimates that she ran up close to $20,000 in medical debt while finishing chemotherapy during the 4 months she was uninsured.

The surgeon she had seen since her diagnosis terminated her care when she could no longer pay her bills. That left her delaying a much-needed mastectomy.

“I don’t sleep at night,” said Ms. Dicks, a single mother of two young kids, ages 3 and 11. “Mentally, I’m drained. Just because I have cancer, doesn’t mean the bills aren’t due every month.”

As soon as she felt well enough over the summer, she started working as a part-time delivery driver for DoorDash to help pay for food and gas.

But that was just a Band-Aid. Even when her new insurance kicked in, covering the costs of daily life remained a struggle.

Ms. Dicks is still in deep medical debt. Her Medicaid has covered new medical expenses, and she hopes Medicaid will reimburse her for the debt she incurred over the summer while she waited for her coverage to kick in. So far, though, Medicaid has not touched her $20,000 debt.

“I fear that I’m not going to be able to dig out of this hole,” Ms. Dicks said.

Researchers who study the financial impacts of cancer have a term for Ms. Dicks’ experience: financial toxicity.

Financial toxicity is a catchall term for the burden many Americans with cancer experience.

“Financial toxicity is a multidimensional concept. There’s both a material burden and a psychosocial one,” said Grace Li Smith, MD, PhD, MPH, a radiation oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Financial toxicity encompasses the direct costs of medical care, including copays, deductibles, and other out-of-pocket expenses for treatment and medications as well as the indirect costs from loss of income or savings associated with cancer care.

Researchers are also now beginning to understand the psychological effects these financial burdens can have on patients and their family.

“Financial toxicity is not unique to the patient,” said Dr. Li Smith. It “very directly impacts the whole family or household.”
 

Stifling financial pressures

Early in her career, Dr. Li Smith was already seeing how her patients’ worries extended beyond their physical disease.

One of Dr. Li Smith’s first patients told her their greatest worry wasn’t whether the treatment would work or what physical toxicity to expect, it was how they would pay for their care.

“There was much more anxiety and true distress about the financial burden than about the treatment itself,” Dr. Li Smith recalled.

This fear about the costs of cancer care is well founded. In the United States, cancer treatment costs reached an estimated $150 billion in 2020 and continue to rise. Patients shoulder a significant portion of that burden – with one study estimating that patients paid $21 billion for their cancer care in 2019.

The burden is often compounded by decreased income. Between 40% and 85% of patients with cancer needed to take time off work or quit their jobs during treatment. And for those, like Dicks, who find themselves with no insurance, out-of-pocket costs can quickly skyrocket.

In fact, one study of newly diagnosed cancer patients over age 50 reported that more than 42% of patients fully depleted their financial assets and around 30% incurred debt by the second year of their diagnosis.

Younger adults may be even more financially vulnerable. A study of patients in Washington found that those under 65 – which represent about half of cancer cases – were two to five times more likely to declare bankruptcy than patients over 65.

Dr. Li Smith and colleagues have found that younger patients aged 18-64 experienced greater monetary hardships, which meant less money for food, worse adherence to medications, as well as greater distress and anxiety overall. In fact, younger adults were over 4.5 times more likely to encounter severe financial toxicity, compared with older adults, and about 4 times more likely to experience severe psychological effects from this burden.

The distress, if left unchecked, can spiral out of control.

Molly MacDonald had just gone through a financially devastating divorce in 2005 when she was diagnosed with breast cancer. Recently out of work and dealing with a $1,300 monthly COBRA premium, the mother of five had no financial safety net. She risked having her car repossessed and her utilities shut off.

“I gave tentative thought to how I could take my life and make it look like an accident,” said Ms. MacDonald. “I thought the kids would be better off without me.”

For some, the loss of income can be even more worrisome than the medical bills. Some patients may go back to work during treatment, often against medical advice.

When Stephanie Caputo, 43, of Monroe, N.J., began treatment for stage III breast cancer in 2021, her physician recommended she stop working. Treatment would make her immunocompromised, and her job in a medical clinic could expose her to harmful pathogens, including the coronavirus.

Ms. Caputo went on disability and received $900 every 2 weeks. But that wasn’t enough to pay her mortgage, let alone cover her other monthly expenses as a single mother of 4 teenagers.

After finishing chemotherapy, and during radiation, Ms. Caputo went back to work, part time, against her doctor’s advice.

“My doctor is telling me I can’t work, but I also can’t have my house go into default,” said Ms. Caputo.

But being on her feet through 12-hour shifts made treatment side effects, especially back and joint pain, kick into overdrive. “The physicality of my job was really difficult to tolerate,” she said.

The physical burden was too great to take on more work, but the extra money also wasn’t enough to keep her afloat. Fortunately, her brother stepped in and covered 6 months of her mortgage payments.
 

Financial toxicity impacts families

Although financial toxicity research to date has largely focused on the patient, researchers are also starting to understand that family members and caregivers often share in the burden.

“We are just at the beginning of realizing that this is a real problem,” said Fumiko Chino, MD, a radiation oncologist at Memorial Sloan Kettering Cancer Center, New York.

Dr. Chino and colleagues recently showed that family members of patients with cancer were more likely to delay or forgo medical care than family members of people without cancer. The study found the effect was greatest among family members of younger adults with cancer.

“The caregiver and family burden related to cancer diagnosis and treatment is really underappreciated,” said Dr. Chino. “Family members and caregivers are neglecting their own health concerns, passing up career opportunities, struggling with financial concerns.”

Dr. Chino speaks from personal experience. When her fiancé, later husband, was diagnosed with neuroendocrine carcinoma in 2005, Dr. Chino quit her job as art director at a television production company to take care of him.

The couple, both in their 20s, struggled to afford his care. Dr. Chino put her own dental, medical, and mental health care on hold. She never, for instance, went to physical therapy to address injuries sustained sleeping in hospital chairs and moving around her husband who was over 6 feet tall. At one point, she walked with a limp.

Dr. Chino’s husband passed away in 2007, and even 15 years later, her injury from sleeping in hospital chairs remains “a significant physical burden,” she said. But like many caregivers “I wasn’t really thinking about my own health.”

Danielle Hadfield, 35, an ED nurse in Rochester, N.Y., also delayed her own care when her mom got sick.

Ms. Hadfield quit her job shortly after her mom was diagnosed with cholangiocarcinoma in August 2020. Ms. Hadfield knew her mom, who lived 3.5 hours away in Albany, N.Y., would need a lot of care in the upcoming months.

“I knew this was going to be the last year or so of her life, and I wanted to be there for her,” said Ms. Hadfield.

When Ms. Hadfield quit her job, she and her husband – who was self-employed – purchased health insurance coverage through the New York state marketplace. The monthly insurance payments for Ms. Hadfield, who was pregnant with her second child, her husband, and their toddler cost as much as the family’s monthly mortgage payments.

In addition to providing childcare for her young daughter and making frequent trips to Albany, Ms. Hadfield began a side business as a legal nurse consultant, working mostly at night, to replace a portion of her lost income. During this time, she began to experience pain attacks that would migrate through her body along with intermittent tongue and facial numbness. She ignored these health issues for nearly a year, until after her mother died in November 2021.

Only after her mother passed away did Ms. Hadfield begin seeking answers to her own pain. In September 2022, she finally got them. She had a nerve condition called small-fiber sensory neuropathy.

But even with a diagnosis, she is still facing more tests to root out the cause and understand the best treatment.
 

Is help out there?

What can physicians do to help patients and families at risk for financial toxicity?

Specific guidelines for dealing with financial toxicity do not exist in most professional guidelines, nor are there standard screening tools to identify it, said Dr. Li Smith.

These gaps put pressure on physicians to ask about financial barriers and concerns, but most do not know how to broach the topic or how to help. “Physicians may not know how to fix the problem or what resources exist,” Dr. Li Smith said.

Patients and family members, on the other hand, are often reluctant to bring up cost with physicians. Some may be ashamed to talk about their financial problems while others may fear doing so will prevent them from being offered the best possible treatments, said Ms. MacDonald.

But, experts say, financial toxicity needs to be dealt with head on. That means involving financial navigators or counselors and social workers who can, for instance, help patients and families find financial support for their basic living expenses.

From a research perspective, more clinical trials should include financial toxicity outcomes, said Joshua Palmer, MD, a radiation oncologist at the University of Michigan, Ann Arbor.

Dr. Palmer and colleagues recently showed that the number of radiation therapy clinical trials including financial toxicity endpoints increased significantly from 2001 to 2020, though the absolute rate of inclusion remains low, at roughly 1.5% of radiation therapy-based clinical trials including financial toxicity endpoints from 2016 to 2020.

“Financial burden is part of the broader discussion about shared decision-making,” said Dr. Palmer.

In shared decision-making, physicians discuss the risks and benefits of different treatment options, empowering the patient to make an informed choice with the physician.

What we want to avoid is patients feeling like they will get inferior care, if they have financial barriers, said Dr. Palmer.

And every little bit can help. In 2006, Ms. MacDonald started the Pink Fund – a nonprofit to help patients with cancer cover nonmedical cost-of-living expenses. Both Ms. Caputo and Ms. Dicks received grants from the Pink Fund. For Ms. Caputo, the funds covered 2 months of car payments and for Ms. Dicks, it covered 2 months of rent.

While the one-time grant was a big help, said Ms. Dicks, “cancer is an everyday thing.” And “we all deserve peace of mind” when trying to heal.

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

When 32-year-old Brittany Dicks was diagnosed with stage II triple negative breast cancer in January 2022, she wasn’t worried about the cost of treatment. A medical assistant in Charleston, S.C., Ms. Dicks had full-time employment with health benefits.

But when she wasn’t able to work for several months because of chemotherapy and its side effects, Ms. Dicks lost her job. Her health insurance coverage ended in May. And although she filed for Medicaid at the beginning of June, it wasn’t approved until September.

Meanwhile, Ms. Dicks still needed treatment. She estimates that she ran up close to $20,000 in medical debt while finishing chemotherapy during the 4 months she was uninsured.

The surgeon she had seen since her diagnosis terminated her care when she could no longer pay her bills. That left her delaying a much-needed mastectomy.

“I don’t sleep at night,” said Ms. Dicks, a single mother of two young kids, ages 3 and 11. “Mentally, I’m drained. Just because I have cancer, doesn’t mean the bills aren’t due every month.”

As soon as she felt well enough over the summer, she started working as a part-time delivery driver for DoorDash to help pay for food and gas.

But that was just a Band-Aid. Even when her new insurance kicked in, covering the costs of daily life remained a struggle.

Ms. Dicks is still in deep medical debt. Her Medicaid has covered new medical expenses, and she hopes Medicaid will reimburse her for the debt she incurred over the summer while she waited for her coverage to kick in. So far, though, Medicaid has not touched her $20,000 debt.

“I fear that I’m not going to be able to dig out of this hole,” Ms. Dicks said.

Researchers who study the financial impacts of cancer have a term for Ms. Dicks’ experience: financial toxicity.

Financial toxicity is a catchall term for the burden many Americans with cancer experience.

“Financial toxicity is a multidimensional concept. There’s both a material burden and a psychosocial one,” said Grace Li Smith, MD, PhD, MPH, a radiation oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Financial toxicity encompasses the direct costs of medical care, including copays, deductibles, and other out-of-pocket expenses for treatment and medications as well as the indirect costs from loss of income or savings associated with cancer care.

Researchers are also now beginning to understand the psychological effects these financial burdens can have on patients and their family.

“Financial toxicity is not unique to the patient,” said Dr. Li Smith. It “very directly impacts the whole family or household.”
 

Stifling financial pressures

Early in her career, Dr. Li Smith was already seeing how her patients’ worries extended beyond their physical disease.

One of Dr. Li Smith’s first patients told her their greatest worry wasn’t whether the treatment would work or what physical toxicity to expect, it was how they would pay for their care.

“There was much more anxiety and true distress about the financial burden than about the treatment itself,” Dr. Li Smith recalled.

This fear about the costs of cancer care is well founded. In the United States, cancer treatment costs reached an estimated $150 billion in 2020 and continue to rise. Patients shoulder a significant portion of that burden – with one study estimating that patients paid $21 billion for their cancer care in 2019.

The burden is often compounded by decreased income. Between 40% and 85% of patients with cancer needed to take time off work or quit their jobs during treatment. And for those, like Dicks, who find themselves with no insurance, out-of-pocket costs can quickly skyrocket.

In fact, one study of newly diagnosed cancer patients over age 50 reported that more than 42% of patients fully depleted their financial assets and around 30% incurred debt by the second year of their diagnosis.

Younger adults may be even more financially vulnerable. A study of patients in Washington found that those under 65 – which represent about half of cancer cases – were two to five times more likely to declare bankruptcy than patients over 65.

Dr. Li Smith and colleagues have found that younger patients aged 18-64 experienced greater monetary hardships, which meant less money for food, worse adherence to medications, as well as greater distress and anxiety overall. In fact, younger adults were over 4.5 times more likely to encounter severe financial toxicity, compared with older adults, and about 4 times more likely to experience severe psychological effects from this burden.

The distress, if left unchecked, can spiral out of control.

Molly MacDonald had just gone through a financially devastating divorce in 2005 when she was diagnosed with breast cancer. Recently out of work and dealing with a $1,300 monthly COBRA premium, the mother of five had no financial safety net. She risked having her car repossessed and her utilities shut off.

“I gave tentative thought to how I could take my life and make it look like an accident,” said Ms. MacDonald. “I thought the kids would be better off without me.”

For some, the loss of income can be even more worrisome than the medical bills. Some patients may go back to work during treatment, often against medical advice.

When Stephanie Caputo, 43, of Monroe, N.J., began treatment for stage III breast cancer in 2021, her physician recommended she stop working. Treatment would make her immunocompromised, and her job in a medical clinic could expose her to harmful pathogens, including the coronavirus.

Ms. Caputo went on disability and received $900 every 2 weeks. But that wasn’t enough to pay her mortgage, let alone cover her other monthly expenses as a single mother of 4 teenagers.

After finishing chemotherapy, and during radiation, Ms. Caputo went back to work, part time, against her doctor’s advice.

“My doctor is telling me I can’t work, but I also can’t have my house go into default,” said Ms. Caputo.

But being on her feet through 12-hour shifts made treatment side effects, especially back and joint pain, kick into overdrive. “The physicality of my job was really difficult to tolerate,” she said.

The physical burden was too great to take on more work, but the extra money also wasn’t enough to keep her afloat. Fortunately, her brother stepped in and covered 6 months of her mortgage payments.
 

Financial toxicity impacts families

Although financial toxicity research to date has largely focused on the patient, researchers are also starting to understand that family members and caregivers often share in the burden.

“We are just at the beginning of realizing that this is a real problem,” said Fumiko Chino, MD, a radiation oncologist at Memorial Sloan Kettering Cancer Center, New York.

Dr. Chino and colleagues recently showed that family members of patients with cancer were more likely to delay or forgo medical care than family members of people without cancer. The study found the effect was greatest among family members of younger adults with cancer.

“The caregiver and family burden related to cancer diagnosis and treatment is really underappreciated,” said Dr. Chino. “Family members and caregivers are neglecting their own health concerns, passing up career opportunities, struggling with financial concerns.”

Dr. Chino speaks from personal experience. When her fiancé, later husband, was diagnosed with neuroendocrine carcinoma in 2005, Dr. Chino quit her job as art director at a television production company to take care of him.

The couple, both in their 20s, struggled to afford his care. Dr. Chino put her own dental, medical, and mental health care on hold. She never, for instance, went to physical therapy to address injuries sustained sleeping in hospital chairs and moving around her husband who was over 6 feet tall. At one point, she walked with a limp.

Dr. Chino’s husband passed away in 2007, and even 15 years later, her injury from sleeping in hospital chairs remains “a significant physical burden,” she said. But like many caregivers “I wasn’t really thinking about my own health.”

Danielle Hadfield, 35, an ED nurse in Rochester, N.Y., also delayed her own care when her mom got sick.

Ms. Hadfield quit her job shortly after her mom was diagnosed with cholangiocarcinoma in August 2020. Ms. Hadfield knew her mom, who lived 3.5 hours away in Albany, N.Y., would need a lot of care in the upcoming months.

“I knew this was going to be the last year or so of her life, and I wanted to be there for her,” said Ms. Hadfield.

When Ms. Hadfield quit her job, she and her husband – who was self-employed – purchased health insurance coverage through the New York state marketplace. The monthly insurance payments for Ms. Hadfield, who was pregnant with her second child, her husband, and their toddler cost as much as the family’s monthly mortgage payments.

In addition to providing childcare for her young daughter and making frequent trips to Albany, Ms. Hadfield began a side business as a legal nurse consultant, working mostly at night, to replace a portion of her lost income. During this time, she began to experience pain attacks that would migrate through her body along with intermittent tongue and facial numbness. She ignored these health issues for nearly a year, until after her mother died in November 2021.

Only after her mother passed away did Ms. Hadfield begin seeking answers to her own pain. In September 2022, she finally got them. She had a nerve condition called small-fiber sensory neuropathy.

But even with a diagnosis, she is still facing more tests to root out the cause and understand the best treatment.
 

Is help out there?

What can physicians do to help patients and families at risk for financial toxicity?

Specific guidelines for dealing with financial toxicity do not exist in most professional guidelines, nor are there standard screening tools to identify it, said Dr. Li Smith.

These gaps put pressure on physicians to ask about financial barriers and concerns, but most do not know how to broach the topic or how to help. “Physicians may not know how to fix the problem or what resources exist,” Dr. Li Smith said.

Patients and family members, on the other hand, are often reluctant to bring up cost with physicians. Some may be ashamed to talk about their financial problems while others may fear doing so will prevent them from being offered the best possible treatments, said Ms. MacDonald.

But, experts say, financial toxicity needs to be dealt with head on. That means involving financial navigators or counselors and social workers who can, for instance, help patients and families find financial support for their basic living expenses.

From a research perspective, more clinical trials should include financial toxicity outcomes, said Joshua Palmer, MD, a radiation oncologist at the University of Michigan, Ann Arbor.

Dr. Palmer and colleagues recently showed that the number of radiation therapy clinical trials including financial toxicity endpoints increased significantly from 2001 to 2020, though the absolute rate of inclusion remains low, at roughly 1.5% of radiation therapy-based clinical trials including financial toxicity endpoints from 2016 to 2020.

“Financial burden is part of the broader discussion about shared decision-making,” said Dr. Palmer.

In shared decision-making, physicians discuss the risks and benefits of different treatment options, empowering the patient to make an informed choice with the physician.

What we want to avoid is patients feeling like they will get inferior care, if they have financial barriers, said Dr. Palmer.

And every little bit can help. In 2006, Ms. MacDonald started the Pink Fund – a nonprofit to help patients with cancer cover nonmedical cost-of-living expenses. Both Ms. Caputo and Ms. Dicks received grants from the Pink Fund. For Ms. Caputo, the funds covered 2 months of car payments and for Ms. Dicks, it covered 2 months of rent.

While the one-time grant was a big help, said Ms. Dicks, “cancer is an everyday thing.” And “we all deserve peace of mind” when trying to heal.

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

When 32-year-old Brittany Dicks was diagnosed with stage II triple negative breast cancer in January 2022, she wasn’t worried about the cost of treatment. A medical assistant in Charleston, S.C., Ms. Dicks had full-time employment with health benefits.

But when she wasn’t able to work for several months because of chemotherapy and its side effects, Ms. Dicks lost her job. Her health insurance coverage ended in May. And although she filed for Medicaid at the beginning of June, it wasn’t approved until September.

Meanwhile, Ms. Dicks still needed treatment. She estimates that she ran up close to $20,000 in medical debt while finishing chemotherapy during the 4 months she was uninsured.

The surgeon she had seen since her diagnosis terminated her care when she could no longer pay her bills. That left her delaying a much-needed mastectomy.

“I don’t sleep at night,” said Ms. Dicks, a single mother of two young kids, ages 3 and 11. “Mentally, I’m drained. Just because I have cancer, doesn’t mean the bills aren’t due every month.”

As soon as she felt well enough over the summer, she started working as a part-time delivery driver for DoorDash to help pay for food and gas.

But that was just a Band-Aid. Even when her new insurance kicked in, covering the costs of daily life remained a struggle.

Ms. Dicks is still in deep medical debt. Her Medicaid has covered new medical expenses, and she hopes Medicaid will reimburse her for the debt she incurred over the summer while she waited for her coverage to kick in. So far, though, Medicaid has not touched her $20,000 debt.

“I fear that I’m not going to be able to dig out of this hole,” Ms. Dicks said.

Researchers who study the financial impacts of cancer have a term for Ms. Dicks’ experience: financial toxicity.

Financial toxicity is a catchall term for the burden many Americans with cancer experience.

“Financial toxicity is a multidimensional concept. There’s both a material burden and a psychosocial one,” said Grace Li Smith, MD, PhD, MPH, a radiation oncologist at the University of Texas MD Anderson Cancer Center, Houston.

Financial toxicity encompasses the direct costs of medical care, including copays, deductibles, and other out-of-pocket expenses for treatment and medications as well as the indirect costs from loss of income or savings associated with cancer care.

Researchers are also now beginning to understand the psychological effects these financial burdens can have on patients and their family.

“Financial toxicity is not unique to the patient,” said Dr. Li Smith. It “very directly impacts the whole family or household.”
 

Stifling financial pressures

Early in her career, Dr. Li Smith was already seeing how her patients’ worries extended beyond their physical disease.

One of Dr. Li Smith’s first patients told her their greatest worry wasn’t whether the treatment would work or what physical toxicity to expect, it was how they would pay for their care.

“There was much more anxiety and true distress about the financial burden than about the treatment itself,” Dr. Li Smith recalled.

This fear about the costs of cancer care is well founded. In the United States, cancer treatment costs reached an estimated $150 billion in 2020 and continue to rise. Patients shoulder a significant portion of that burden – with one study estimating that patients paid $21 billion for their cancer care in 2019.

The burden is often compounded by decreased income. Between 40% and 85% of patients with cancer needed to take time off work or quit their jobs during treatment. And for those, like Dicks, who find themselves with no insurance, out-of-pocket costs can quickly skyrocket.

In fact, one study of newly diagnosed cancer patients over age 50 reported that more than 42% of patients fully depleted their financial assets and around 30% incurred debt by the second year of their diagnosis.

Younger adults may be even more financially vulnerable. A study of patients in Washington found that those under 65 – which represent about half of cancer cases – were two to five times more likely to declare bankruptcy than patients over 65.

Dr. Li Smith and colleagues have found that younger patients aged 18-64 experienced greater monetary hardships, which meant less money for food, worse adherence to medications, as well as greater distress and anxiety overall. In fact, younger adults were over 4.5 times more likely to encounter severe financial toxicity, compared with older adults, and about 4 times more likely to experience severe psychological effects from this burden.

The distress, if left unchecked, can spiral out of control.

Molly MacDonald had just gone through a financially devastating divorce in 2005 when she was diagnosed with breast cancer. Recently out of work and dealing with a $1,300 monthly COBRA premium, the mother of five had no financial safety net. She risked having her car repossessed and her utilities shut off.

“I gave tentative thought to how I could take my life and make it look like an accident,” said Ms. MacDonald. “I thought the kids would be better off without me.”

For some, the loss of income can be even more worrisome than the medical bills. Some patients may go back to work during treatment, often against medical advice.

When Stephanie Caputo, 43, of Monroe, N.J., began treatment for stage III breast cancer in 2021, her physician recommended she stop working. Treatment would make her immunocompromised, and her job in a medical clinic could expose her to harmful pathogens, including the coronavirus.

Ms. Caputo went on disability and received $900 every 2 weeks. But that wasn’t enough to pay her mortgage, let alone cover her other monthly expenses as a single mother of 4 teenagers.

After finishing chemotherapy, and during radiation, Ms. Caputo went back to work, part time, against her doctor’s advice.

“My doctor is telling me I can’t work, but I also can’t have my house go into default,” said Ms. Caputo.

But being on her feet through 12-hour shifts made treatment side effects, especially back and joint pain, kick into overdrive. “The physicality of my job was really difficult to tolerate,” she said.

The physical burden was too great to take on more work, but the extra money also wasn’t enough to keep her afloat. Fortunately, her brother stepped in and covered 6 months of her mortgage payments.
 

Financial toxicity impacts families

Although financial toxicity research to date has largely focused on the patient, researchers are also starting to understand that family members and caregivers often share in the burden.

“We are just at the beginning of realizing that this is a real problem,” said Fumiko Chino, MD, a radiation oncologist at Memorial Sloan Kettering Cancer Center, New York.

Dr. Chino and colleagues recently showed that family members of patients with cancer were more likely to delay or forgo medical care than family members of people without cancer. The study found the effect was greatest among family members of younger adults with cancer.

“The caregiver and family burden related to cancer diagnosis and treatment is really underappreciated,” said Dr. Chino. “Family members and caregivers are neglecting their own health concerns, passing up career opportunities, struggling with financial concerns.”

Dr. Chino speaks from personal experience. When her fiancé, later husband, was diagnosed with neuroendocrine carcinoma in 2005, Dr. Chino quit her job as art director at a television production company to take care of him.

The couple, both in their 20s, struggled to afford his care. Dr. Chino put her own dental, medical, and mental health care on hold. She never, for instance, went to physical therapy to address injuries sustained sleeping in hospital chairs and moving around her husband who was over 6 feet tall. At one point, she walked with a limp.

Dr. Chino’s husband passed away in 2007, and even 15 years later, her injury from sleeping in hospital chairs remains “a significant physical burden,” she said. But like many caregivers “I wasn’t really thinking about my own health.”

Danielle Hadfield, 35, an ED nurse in Rochester, N.Y., also delayed her own care when her mom got sick.

Ms. Hadfield quit her job shortly after her mom was diagnosed with cholangiocarcinoma in August 2020. Ms. Hadfield knew her mom, who lived 3.5 hours away in Albany, N.Y., would need a lot of care in the upcoming months.

“I knew this was going to be the last year or so of her life, and I wanted to be there for her,” said Ms. Hadfield.

When Ms. Hadfield quit her job, she and her husband – who was self-employed – purchased health insurance coverage through the New York state marketplace. The monthly insurance payments for Ms. Hadfield, who was pregnant with her second child, her husband, and their toddler cost as much as the family’s monthly mortgage payments.

In addition to providing childcare for her young daughter and making frequent trips to Albany, Ms. Hadfield began a side business as a legal nurse consultant, working mostly at night, to replace a portion of her lost income. During this time, she began to experience pain attacks that would migrate through her body along with intermittent tongue and facial numbness. She ignored these health issues for nearly a year, until after her mother died in November 2021.

Only after her mother passed away did Ms. Hadfield begin seeking answers to her own pain. In September 2022, she finally got them. She had a nerve condition called small-fiber sensory neuropathy.

But even with a diagnosis, she is still facing more tests to root out the cause and understand the best treatment.
 

Is help out there?

What can physicians do to help patients and families at risk for financial toxicity?

Specific guidelines for dealing with financial toxicity do not exist in most professional guidelines, nor are there standard screening tools to identify it, said Dr. Li Smith.

These gaps put pressure on physicians to ask about financial barriers and concerns, but most do not know how to broach the topic or how to help. “Physicians may not know how to fix the problem or what resources exist,” Dr. Li Smith said.

Patients and family members, on the other hand, are often reluctant to bring up cost with physicians. Some may be ashamed to talk about their financial problems while others may fear doing so will prevent them from being offered the best possible treatments, said Ms. MacDonald.

But, experts say, financial toxicity needs to be dealt with head on. That means involving financial navigators or counselors and social workers who can, for instance, help patients and families find financial support for their basic living expenses.

From a research perspective, more clinical trials should include financial toxicity outcomes, said Joshua Palmer, MD, a radiation oncologist at the University of Michigan, Ann Arbor.

Dr. Palmer and colleagues recently showed that the number of radiation therapy clinical trials including financial toxicity endpoints increased significantly from 2001 to 2020, though the absolute rate of inclusion remains low, at roughly 1.5% of radiation therapy-based clinical trials including financial toxicity endpoints from 2016 to 2020.

“Financial burden is part of the broader discussion about shared decision-making,” said Dr. Palmer.

In shared decision-making, physicians discuss the risks and benefits of different treatment options, empowering the patient to make an informed choice with the physician.

What we want to avoid is patients feeling like they will get inferior care, if they have financial barriers, said Dr. Palmer.

And every little bit can help. In 2006, Ms. MacDonald started the Pink Fund – a nonprofit to help patients with cancer cover nonmedical cost-of-living expenses. Both Ms. Caputo and Ms. Dicks received grants from the Pink Fund. For Ms. Caputo, the funds covered 2 months of car payments and for Ms. Dicks, it covered 2 months of rent.

While the one-time grant was a big help, said Ms. Dicks, “cancer is an everyday thing.” And “we all deserve peace of mind” when trying to heal.

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

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

SAN DIEGO—Don’t stand when you talk at bedside. Ditch the white gowns, turn away from your computers and pagers, and stop yourself from interrupting all the time.

These tips—and more—can help clinicians provide better and more effective care, said a colorectal surgeon who spoke about communication skills at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Research has suggested that nearly half of Americans don’t think their health care practitioners (HCPs) are compassionate, “and that’s really sad,” said Lorene Valdez-Boyle, MD, MS, surgery chief at the New Mexico VA Health Care Service.

To combat this perception, she said, HCPs can adopt multiple strategies as they work with veterans and their families. The goal, she said, is “to try to get them to trust you and want to be part of their treatment. This is how we're going to have better outcomes.”

Some strategies are simple. Dr. Valdez-Boyle, for example, doesn’t wear a white gown when she sees patients. “Obviously, they’re really gross,” she said. “But also, I want them to be comfortable with me. I sit down at their level, and we have a conversation. We talk about our dogs and we bond, because that’s going to help them trust me and want to work with me. I do that with families too. We joke, and we laugh.”

Sitting bedside instead of standing is important, she said, and a 2016 study backs up this idea. “It’s difficult when you’re running around or you want to get to the next one, and the patient just keeps talking,” she said. But research showed that “when the clinician sat, the patient felt like they listened more carefully, and they explained things in a better way that was much easier for them to understand. They definitely had an improved perception of their [clinician’s] communication skills.”

She highlighted another 2016 study that examined a Commit to Sit initiative in which nurses were urged to sit with patients during each shift. Nurse communication scores and overall patient experience scores went up.

The VA now has a Commit to Sit initiative, which urges clinicians to put away computers, smart phones, and pagers. “The patient feels that we’ve listened more intently to their concerns and care more about them as a patient,” Dr. Valdez-Boyle said. “We have an improved understanding of their health as a result of this. It allows the site employee to continue to be efficient while still delivering compassionate care and fosters trusted relationships in an empathetic and respectful manner.”

For more about the initiative, visit the VA PX SharePoint.

The VA, she said, also has a Take a Moment initiative that emphasizes eye contact, face-to-face interaction without electronics for at least the first 5 minutes of each visit, and seated conversations.

Dr. Valdez-Boyle also urged colleagues to pay attention to how often they interrupt. She pointed to a 2019 study that reported that patients had a median of 11 seconds—yes, seconds—to explain their problem in two-thirds of clinician encounters. “I think some of it is because we think we know what they're going to say.”

In the age of COVID-19, she suggested turning to fist or elbow bumps instead of handshakes. And she said, let patients wear street clothes when appropriate so they’re more comfortable. 

In the big picture, she said, good communication and a commitment to shared decision making “really create a shared responsibility. They give your patients ownership over their disease and the ability to make the decisions with their team.

Dr. Valdez-Boyle reported no disclosures.

SAN DIEGO—Don’t stand when you talk at bedside. Ditch the white gowns, turn away from your computers and pagers, and stop yourself from interrupting all the time.

These tips—and more—can help clinicians provide better and more effective care, said a colorectal surgeon who spoke about communication skills at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Research has suggested that nearly half of Americans don’t think their health care practitioners (HCPs) are compassionate, “and that’s really sad,” said Lorene Valdez-Boyle, MD, MS, surgery chief at the New Mexico VA Health Care Service.

To combat this perception, she said, HCPs can adopt multiple strategies as they work with veterans and their families. The goal, she said, is “to try to get them to trust you and want to be part of their treatment. This is how we're going to have better outcomes.”

Some strategies are simple. Dr. Valdez-Boyle, for example, doesn’t wear a white gown when she sees patients. “Obviously, they’re really gross,” she said. “But also, I want them to be comfortable with me. I sit down at their level, and we have a conversation. We talk about our dogs and we bond, because that’s going to help them trust me and want to work with me. I do that with families too. We joke, and we laugh.”

Sitting bedside instead of standing is important, she said, and a 2016 study backs up this idea. “It’s difficult when you’re running around or you want to get to the next one, and the patient just keeps talking,” she said. But research showed that “when the clinician sat, the patient felt like they listened more carefully, and they explained things in a better way that was much easier for them to understand. They definitely had an improved perception of their [clinician’s] communication skills.”

She highlighted another 2016 study that examined a Commit to Sit initiative in which nurses were urged to sit with patients during each shift. Nurse communication scores and overall patient experience scores went up.

The VA now has a Commit to Sit initiative, which urges clinicians to put away computers, smart phones, and pagers. “The patient feels that we’ve listened more intently to their concerns and care more about them as a patient,” Dr. Valdez-Boyle said. “We have an improved understanding of their health as a result of this. It allows the site employee to continue to be efficient while still delivering compassionate care and fosters trusted relationships in an empathetic and respectful manner.”

For more about the initiative, visit the VA PX SharePoint.

The VA, she said, also has a Take a Moment initiative that emphasizes eye contact, face-to-face interaction without electronics for at least the first 5 minutes of each visit, and seated conversations.

Dr. Valdez-Boyle also urged colleagues to pay attention to how often they interrupt. She pointed to a 2019 study that reported that patients had a median of 11 seconds—yes, seconds—to explain their problem in two-thirds of clinician encounters. “I think some of it is because we think we know what they're going to say.”

In the age of COVID-19, she suggested turning to fist or elbow bumps instead of handshakes. And she said, let patients wear street clothes when appropriate so they’re more comfortable. 

In the big picture, she said, good communication and a commitment to shared decision making “really create a shared responsibility. They give your patients ownership over their disease and the ability to make the decisions with their team.

Dr. Valdez-Boyle reported no disclosures.

SAN DIEGO—Don’t stand when you talk at bedside. Ditch the white gowns, turn away from your computers and pagers, and stop yourself from interrupting all the time.

These tips—and more—can help clinicians provide better and more effective care, said a colorectal surgeon who spoke about communication skills at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Research has suggested that nearly half of Americans don’t think their health care practitioners (HCPs) are compassionate, “and that’s really sad,” said Lorene Valdez-Boyle, MD, MS, surgery chief at the New Mexico VA Health Care Service.

To combat this perception, she said, HCPs can adopt multiple strategies as they work with veterans and their families. The goal, she said, is “to try to get them to trust you and want to be part of their treatment. This is how we're going to have better outcomes.”

Some strategies are simple. Dr. Valdez-Boyle, for example, doesn’t wear a white gown when she sees patients. “Obviously, they’re really gross,” she said. “But also, I want them to be comfortable with me. I sit down at their level, and we have a conversation. We talk about our dogs and we bond, because that’s going to help them trust me and want to work with me. I do that with families too. We joke, and we laugh.”

Sitting bedside instead of standing is important, she said, and a 2016 study backs up this idea. “It’s difficult when you’re running around or you want to get to the next one, and the patient just keeps talking,” she said. But research showed that “when the clinician sat, the patient felt like they listened more carefully, and they explained things in a better way that was much easier for them to understand. They definitely had an improved perception of their [clinician’s] communication skills.”

She highlighted another 2016 study that examined a Commit to Sit initiative in which nurses were urged to sit with patients during each shift. Nurse communication scores and overall patient experience scores went up.

The VA now has a Commit to Sit initiative, which urges clinicians to put away computers, smart phones, and pagers. “The patient feels that we’ve listened more intently to their concerns and care more about them as a patient,” Dr. Valdez-Boyle said. “We have an improved understanding of their health as a result of this. It allows the site employee to continue to be efficient while still delivering compassionate care and fosters trusted relationships in an empathetic and respectful manner.”

For more about the initiative, visit the VA PX SharePoint.

The VA, she said, also has a Take a Moment initiative that emphasizes eye contact, face-to-face interaction without electronics for at least the first 5 minutes of each visit, and seated conversations.

Dr. Valdez-Boyle also urged colleagues to pay attention to how often they interrupt. She pointed to a 2019 study that reported that patients had a median of 11 seconds—yes, seconds—to explain their problem in two-thirds of clinician encounters. “I think some of it is because we think we know what they're going to say.”

In the age of COVID-19, she suggested turning to fist or elbow bumps instead of handshakes. And she said, let patients wear street clothes when appropriate so they’re more comfortable. 

In the big picture, she said, good communication and a commitment to shared decision making “really create a shared responsibility. They give your patients ownership over their disease and the ability to make the decisions with their team.

Dr. Valdez-Boyle reported no disclosures.

The effects of the Russian invasion of Ukraine have been devastating, with the loss of tens of thousands of civilian lives and about one-third of the population having been displaced. The war has put a great strain on health care in the country.

“The Russian army is targeting civilian infrastructure, trying to plunge Ukrainians into cold and darkness. (It) is also deliberately targeting hospitals and clinics in Ukraine,” said Nataliya Kovalchuk, PhD, during a session on Ukraine health care at the annual meeting of the American Society for Radiation Oncology held this week in San Antonio. She is a clinical associate professor of radiation oncology at Stanford (Calif.) University.

Analysis of previous wars have shown an increase in cancer incidence and mortality, and the same should be expected in the future in Ukraine, according to Ruslan Zelinskyi, MS, who is president of the Ukrainian Association of Medical Physicists and practices at Spizhenko Clinic in Ukraine. “We must prepare for it now, and we do it. During the full-scale war in Ukraine, three new linear accelerators were installed and put into clinical use,” he said during his talk.

He also gave a personal perspective of the terrible conditions and choices facing Ukrainian health care workers. “I have often heard that science is outside of politics. Perhaps in peacetime, but when fragments of missiles pass through the wall” – here, Mr. Zelinskyi paused to swing the camera around to show bomb damage on the walls of the room where he was conducting his virtual talk – “it is impossible to be outside of politics when 900 medical facilities were destroyed or damaged.” Health care workers have been killed, and patients have lost months or years because they could not receive medical care.

That reality is forcing Ukrainians to make choices most health care workers would struggle to imagine. “For many years, I put on medical clothes and fight against cancer. But (for) me comes the moment when I will change my medical clothes to military (clothes), like many, many other Ukrainians of various professions, because we must preserve the freedom of Ukraine and the security of Europe to do science in a peaceful world,” Mr. Zelinskyi said.

Following Mr. Zelinskyi’s talk, Asya Agulnik, MD, MPH, director of the St. Jude’s Global Critical Care Program and a pediatric intensivist at St. Jude’s Children’s Research Hospital, Memphis, described St. Jude’s efforts with pediatric cancer patients. St. Jude’s Global Critical Care Program created a Eurasian Regional Program in 2018 to serve Central Asia and Eastern Europe, which now includes 48 institutions and more than 250 clinicians and members that help care for children with cancer.

In the aftermath of the invasion, the Eurasian Regional Program launched the Safer Ukraine network to ensure continued care for children with cancer and blood disorders. Initially, the patient’s family or physician identifies a child has having a medical need that cannot be met locally and requiring evacuation. The nongovernmental organization Tabletochki, which has worked with children with cancer in Ukraine since 2011, then arranges transport of the child and his or her medical records to the Ukrainian Specialized Children’s Center in Lviv, Ukraine, for evaluation and stabilization. From there, patients along with their mother and sometimes siblings are transferred to Poland. Transportation methods include ambulance, helicopter, bus, and medical trains that have a full intensive care unit aboard.

In Poland, hospitals estimated they could take on another 200 patients without compromising care for their existing patients, but evacuations reached that number within the first few weeks of the war. It was clear patients would have to be transferred to other countries. To do that, Safer Ukraine set up the Unicorn Marian Wilemski Clinic, which is a converted hotel operated as a partnership between many foundations and governments. It sends unstable patients to nearby emergency rooms, and stable patients stay at the clinic until they can be evaluated and matched with an international care provider from a registry of more than 200 hospitals in 29 countries that have agreed to take patients. A 24/7 Zoom call began on the first day of the war, initially staffed by St. Jude volunteers and now by a contractor. It serves as a command center.

Over the first 12 weeks of the war, the program evacuated over 1,000 children, and over 200 medical records per week were being translated at peak activity. Nearly 300 patients went to Poland, and the rest to 18 countries in Europe and North America.

The success of the initiative stems in part from the fact that it leveraged preexisting collaborations that focused on childhood cancer, according to Dr. Agulnik. “Many stakeholders that came together had previously worked together, but then quickly came together around this unified initiative with the goal of helping these patients,” she said during her talk.

Roman Kowalchuk, MD, who is a radiation oncology resident at Mayo Clinic, spoke about telemedicine efforts to assist physicians and patients in Ukraine.

“I’ve been especially interested in trying to help through telemedicine. We have so much expertise, so many things that we can offer, even if we can’t be there physically, through some of these avenues that really, especially through COVID, have been further developed in terms of virtual support, virtual expertise, and consultations. That presents the opportunity to be able to share some of that knowledge, some of that expertise, to help clinical care in Ukraine given the current circumstance,” said Dr. Kowalchuk during his presentation.

Efforts have used technology like the telemedicine platform Viveo, based in Estonia. One app, called HealUA, takes descriptions from physicians needing advice, and volunteers can scroll through inquiries and provide input. This is especially useful since most physicians in Ukraine are generalists, according to Dr. Kowalchuk, and so may need assistance with diagnosis and management of rare conditions.

Other telehealth approaches include TeleHelp Ukraine. There are WhatsApp groups with hundreds of volunteers who translate Ukrainian medical records to other languages to help non-Ukrainian physicians understand a patient’s history. Expertise is also needed in engineering, emergency medicine, surgery, various fields of oncology, and other specialties. Dr. Kowalchuk noted that Good Samaritan laws generally shield volunteers in these types of programs from legal liability.

International hospital networks taking part in these efforts include St. Jude, European Cancer Organization, American Cancer Society, American Society for Clinical Oncology, and ASTRO.

None of the presenters have relevant financial disclosures.

The effects of the Russian invasion of Ukraine have been devastating, with the loss of tens of thousands of civilian lives and about one-third of the population having been displaced. The war has put a great strain on health care in the country.

“The Russian army is targeting civilian infrastructure, trying to plunge Ukrainians into cold and darkness. (It) is also deliberately targeting hospitals and clinics in Ukraine,” said Nataliya Kovalchuk, PhD, during a session on Ukraine health care at the annual meeting of the American Society for Radiation Oncology held this week in San Antonio. She is a clinical associate professor of radiation oncology at Stanford (Calif.) University.

Analysis of previous wars have shown an increase in cancer incidence and mortality, and the same should be expected in the future in Ukraine, according to Ruslan Zelinskyi, MS, who is president of the Ukrainian Association of Medical Physicists and practices at Spizhenko Clinic in Ukraine. “We must prepare for it now, and we do it. During the full-scale war in Ukraine, three new linear accelerators were installed and put into clinical use,” he said during his talk.

He also gave a personal perspective of the terrible conditions and choices facing Ukrainian health care workers. “I have often heard that science is outside of politics. Perhaps in peacetime, but when fragments of missiles pass through the wall” – here, Mr. Zelinskyi paused to swing the camera around to show bomb damage on the walls of the room where he was conducting his virtual talk – “it is impossible to be outside of politics when 900 medical facilities were destroyed or damaged.” Health care workers have been killed, and patients have lost months or years because they could not receive medical care.

That reality is forcing Ukrainians to make choices most health care workers would struggle to imagine. “For many years, I put on medical clothes and fight against cancer. But (for) me comes the moment when I will change my medical clothes to military (clothes), like many, many other Ukrainians of various professions, because we must preserve the freedom of Ukraine and the security of Europe to do science in a peaceful world,” Mr. Zelinskyi said.

Following Mr. Zelinskyi’s talk, Asya Agulnik, MD, MPH, director of the St. Jude’s Global Critical Care Program and a pediatric intensivist at St. Jude’s Children’s Research Hospital, Memphis, described St. Jude’s efforts with pediatric cancer patients. St. Jude’s Global Critical Care Program created a Eurasian Regional Program in 2018 to serve Central Asia and Eastern Europe, which now includes 48 institutions and more than 250 clinicians and members that help care for children with cancer.

In the aftermath of the invasion, the Eurasian Regional Program launched the Safer Ukraine network to ensure continued care for children with cancer and blood disorders. Initially, the patient’s family or physician identifies a child has having a medical need that cannot be met locally and requiring evacuation. The nongovernmental organization Tabletochki, which has worked with children with cancer in Ukraine since 2011, then arranges transport of the child and his or her medical records to the Ukrainian Specialized Children’s Center in Lviv, Ukraine, for evaluation and stabilization. From there, patients along with their mother and sometimes siblings are transferred to Poland. Transportation methods include ambulance, helicopter, bus, and medical trains that have a full intensive care unit aboard.

In Poland, hospitals estimated they could take on another 200 patients without compromising care for their existing patients, but evacuations reached that number within the first few weeks of the war. It was clear patients would have to be transferred to other countries. To do that, Safer Ukraine set up the Unicorn Marian Wilemski Clinic, which is a converted hotel operated as a partnership between many foundations and governments. It sends unstable patients to nearby emergency rooms, and stable patients stay at the clinic until they can be evaluated and matched with an international care provider from a registry of more than 200 hospitals in 29 countries that have agreed to take patients. A 24/7 Zoom call began on the first day of the war, initially staffed by St. Jude volunteers and now by a contractor. It serves as a command center.

Over the first 12 weeks of the war, the program evacuated over 1,000 children, and over 200 medical records per week were being translated at peak activity. Nearly 300 patients went to Poland, and the rest to 18 countries in Europe and North America.

The success of the initiative stems in part from the fact that it leveraged preexisting collaborations that focused on childhood cancer, according to Dr. Agulnik. “Many stakeholders that came together had previously worked together, but then quickly came together around this unified initiative with the goal of helping these patients,” she said during her talk.

Roman Kowalchuk, MD, who is a radiation oncology resident at Mayo Clinic, spoke about telemedicine efforts to assist physicians and patients in Ukraine.

“I’ve been especially interested in trying to help through telemedicine. We have so much expertise, so many things that we can offer, even if we can’t be there physically, through some of these avenues that really, especially through COVID, have been further developed in terms of virtual support, virtual expertise, and consultations. That presents the opportunity to be able to share some of that knowledge, some of that expertise, to help clinical care in Ukraine given the current circumstance,” said Dr. Kowalchuk during his presentation.

Efforts have used technology like the telemedicine platform Viveo, based in Estonia. One app, called HealUA, takes descriptions from physicians needing advice, and volunteers can scroll through inquiries and provide input. This is especially useful since most physicians in Ukraine are generalists, according to Dr. Kowalchuk, and so may need assistance with diagnosis and management of rare conditions.

Other telehealth approaches include TeleHelp Ukraine. There are WhatsApp groups with hundreds of volunteers who translate Ukrainian medical records to other languages to help non-Ukrainian physicians understand a patient’s history. Expertise is also needed in engineering, emergency medicine, surgery, various fields of oncology, and other specialties. Dr. Kowalchuk noted that Good Samaritan laws generally shield volunteers in these types of programs from legal liability.

International hospital networks taking part in these efforts include St. Jude, European Cancer Organization, American Cancer Society, American Society for Clinical Oncology, and ASTRO.

None of the presenters have relevant financial disclosures.

The effects of the Russian invasion of Ukraine have been devastating, with the loss of tens of thousands of civilian lives and about one-third of the population having been displaced. The war has put a great strain on health care in the country.

“The Russian army is targeting civilian infrastructure, trying to plunge Ukrainians into cold and darkness. (It) is also deliberately targeting hospitals and clinics in Ukraine,” said Nataliya Kovalchuk, PhD, during a session on Ukraine health care at the annual meeting of the American Society for Radiation Oncology held this week in San Antonio. She is a clinical associate professor of radiation oncology at Stanford (Calif.) University.

Analysis of previous wars have shown an increase in cancer incidence and mortality, and the same should be expected in the future in Ukraine, according to Ruslan Zelinskyi, MS, who is president of the Ukrainian Association of Medical Physicists and practices at Spizhenko Clinic in Ukraine. “We must prepare for it now, and we do it. During the full-scale war in Ukraine, three new linear accelerators were installed and put into clinical use,” he said during his talk.

He also gave a personal perspective of the terrible conditions and choices facing Ukrainian health care workers. “I have often heard that science is outside of politics. Perhaps in peacetime, but when fragments of missiles pass through the wall” – here, Mr. Zelinskyi paused to swing the camera around to show bomb damage on the walls of the room where he was conducting his virtual talk – “it is impossible to be outside of politics when 900 medical facilities were destroyed or damaged.” Health care workers have been killed, and patients have lost months or years because they could not receive medical care.

That reality is forcing Ukrainians to make choices most health care workers would struggle to imagine. “For many years, I put on medical clothes and fight against cancer. But (for) me comes the moment when I will change my medical clothes to military (clothes), like many, many other Ukrainians of various professions, because we must preserve the freedom of Ukraine and the security of Europe to do science in a peaceful world,” Mr. Zelinskyi said.

Following Mr. Zelinskyi’s talk, Asya Agulnik, MD, MPH, director of the St. Jude’s Global Critical Care Program and a pediatric intensivist at St. Jude’s Children’s Research Hospital, Memphis, described St. Jude’s efforts with pediatric cancer patients. St. Jude’s Global Critical Care Program created a Eurasian Regional Program in 2018 to serve Central Asia and Eastern Europe, which now includes 48 institutions and more than 250 clinicians and members that help care for children with cancer.

In the aftermath of the invasion, the Eurasian Regional Program launched the Safer Ukraine network to ensure continued care for children with cancer and blood disorders. Initially, the patient’s family or physician identifies a child has having a medical need that cannot be met locally and requiring evacuation. The nongovernmental organization Tabletochki, which has worked with children with cancer in Ukraine since 2011, then arranges transport of the child and his or her medical records to the Ukrainian Specialized Children’s Center in Lviv, Ukraine, for evaluation and stabilization. From there, patients along with their mother and sometimes siblings are transferred to Poland. Transportation methods include ambulance, helicopter, bus, and medical trains that have a full intensive care unit aboard.

In Poland, hospitals estimated they could take on another 200 patients without compromising care for their existing patients, but evacuations reached that number within the first few weeks of the war. It was clear patients would have to be transferred to other countries. To do that, Safer Ukraine set up the Unicorn Marian Wilemski Clinic, which is a converted hotel operated as a partnership between many foundations and governments. It sends unstable patients to nearby emergency rooms, and stable patients stay at the clinic until they can be evaluated and matched with an international care provider from a registry of more than 200 hospitals in 29 countries that have agreed to take patients. A 24/7 Zoom call began on the first day of the war, initially staffed by St. Jude volunteers and now by a contractor. It serves as a command center.

Over the first 12 weeks of the war, the program evacuated over 1,000 children, and over 200 medical records per week were being translated at peak activity. Nearly 300 patients went to Poland, and the rest to 18 countries in Europe and North America.

The success of the initiative stems in part from the fact that it leveraged preexisting collaborations that focused on childhood cancer, according to Dr. Agulnik. “Many stakeholders that came together had previously worked together, but then quickly came together around this unified initiative with the goal of helping these patients,” she said during her talk.

Roman Kowalchuk, MD, who is a radiation oncology resident at Mayo Clinic, spoke about telemedicine efforts to assist physicians and patients in Ukraine.

“I’ve been especially interested in trying to help through telemedicine. We have so much expertise, so many things that we can offer, even if we can’t be there physically, through some of these avenues that really, especially through COVID, have been further developed in terms of virtual support, virtual expertise, and consultations. That presents the opportunity to be able to share some of that knowledge, some of that expertise, to help clinical care in Ukraine given the current circumstance,” said Dr. Kowalchuk during his presentation.

Efforts have used technology like the telemedicine platform Viveo, based in Estonia. One app, called HealUA, takes descriptions from physicians needing advice, and volunteers can scroll through inquiries and provide input. This is especially useful since most physicians in Ukraine are generalists, according to Dr. Kowalchuk, and so may need assistance with diagnosis and management of rare conditions.

Other telehealth approaches include TeleHelp Ukraine. There are WhatsApp groups with hundreds of volunteers who translate Ukrainian medical records to other languages to help non-Ukrainian physicians understand a patient’s history. Expertise is also needed in engineering, emergency medicine, surgery, various fields of oncology, and other specialties. Dr. Kowalchuk noted that Good Samaritan laws generally shield volunteers in these types of programs from legal liability.

International hospital networks taking part in these efforts include St. Jude, European Cancer Organization, American Cancer Society, American Society for Clinical Oncology, and ASTRO.

None of the presenters have relevant financial disclosures.

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10 

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10 

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10