Pediatrics

TOPLINE:

The use of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for treating juvenile idiopathic arthritis (JIA) rose sharply from 2001 to 2022, while the use of conventional synthetic DMARDs (csDMARDs) plummeted, with adalimumab becoming the most commonly used b/tsDMARD.

METHODOLOGY:

• Researchers performed a serial cross-sectional study using Merative MarketScan Commercial Claims and Encounters data from 2000 to 2022 to describe recent trends in DMARD use for children with JIA in the United States.
• They identified 20,258 new episodes of DMARD use among 13,696 children with JIA (median age, 14 years; 67.5% girls) who newly initiated at least one DMARD.
• Participants were required to have ≥ 365 days of continuous healthcare and pharmacy eligibility prior to the index date, defined as the date of DMARD initiation.

TAKEAWAY:

• The use of csDMARDs declined from 89.5% to 43.2% between 2001 and 2022 (P < .001 for trend), whereas the use of bDMARDs increased from 10.5% to 50.0% over the same period (P < .001).
• Methotrexate was the most commonly used DMARD throughout the study period ; however, as with other csDMARDs, its use declined from 42.1% in 2001 to 21.5% in 2022 (P < .001 ).
• Use of the tumor necrosis factor inhibitor adalimumab doubled from 7% in 2007 to 14% in 2008 and increased further up to 20.5% by 2022; adalimumab also became the most predominantly used b/tsDMARD after csDMARD monotherapy, accounting for 77.8% of prescriptions following csDMARDs in 2022.
• Even though the use of individual TNF inhibitors increased, their overall popularity fell in recent years as the use of newer b/tsDMARDs, such as ustekinumab and secukinumab, increased.

IN PRACTICE:

“These real-world treatment patterns give us insight into how selection of therapies for JIA has evolved with increasing availability of effective agents and help prepare for future studies on comparative DMARD safety and effectiveness,” the authors wrote.

SOURCE:

The study was led by Priyanka Yalamanchili, PharmD, MS, Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Rutgers University, New Brunswick, New Jersey, and was published online October 22, 2024, in Arthritis & Rheumatology.

LIMITATIONS: 

The dependence on commercial claims data may have limited the generalizability of the findings to other populations, such as those with public insurance or without insurance. The study did not have access to demographic data of the participants to investigate the presence of disparities in the use of DMARDs. Moreover, the lack of clinical details about the patients with JIA, including disease severity and specialty of prescribers, may have affected the interpretation of the results.

DISCLOSURES:

The study was supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and several other institutes of the National Institutes of Health, as well as the Rheumatology Research Foundation and the Juvenile Diabetes Research Foundation. No conflicts of interest were reported by the authors.

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

TOPLINE:

The use of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for treating juvenile idiopathic arthritis (JIA) rose sharply from 2001 to 2022, while the use of conventional synthetic DMARDs (csDMARDs) plummeted, with adalimumab becoming the most commonly used b/tsDMARD.

METHODOLOGY:

• Researchers performed a serial cross-sectional study using Merative MarketScan Commercial Claims and Encounters data from 2000 to 2022 to describe recent trends in DMARD use for children with JIA in the United States.
• They identified 20,258 new episodes of DMARD use among 13,696 children with JIA (median age, 14 years; 67.5% girls) who newly initiated at least one DMARD.
• Participants were required to have ≥ 365 days of continuous healthcare and pharmacy eligibility prior to the index date, defined as the date of DMARD initiation.

TAKEAWAY:

• The use of csDMARDs declined from 89.5% to 43.2% between 2001 and 2022 (P < .001 for trend), whereas the use of bDMARDs increased from 10.5% to 50.0% over the same period (P < .001).
• Methotrexate was the most commonly used DMARD throughout the study period ; however, as with other csDMARDs, its use declined from 42.1% in 2001 to 21.5% in 2022 (P < .001 ).
• Use of the tumor necrosis factor inhibitor adalimumab doubled from 7% in 2007 to 14% in 2008 and increased further up to 20.5% by 2022; adalimumab also became the most predominantly used b/tsDMARD after csDMARD monotherapy, accounting for 77.8% of prescriptions following csDMARDs in 2022.
• Even though the use of individual TNF inhibitors increased, their overall popularity fell in recent years as the use of newer b/tsDMARDs, such as ustekinumab and secukinumab, increased.

IN PRACTICE:

“These real-world treatment patterns give us insight into how selection of therapies for JIA has evolved with increasing availability of effective agents and help prepare for future studies on comparative DMARD safety and effectiveness,” the authors wrote.

SOURCE:

The study was led by Priyanka Yalamanchili, PharmD, MS, Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Rutgers University, New Brunswick, New Jersey, and was published online October 22, 2024, in Arthritis & Rheumatology.

LIMITATIONS: 

The dependence on commercial claims data may have limited the generalizability of the findings to other populations, such as those with public insurance or without insurance. The study did not have access to demographic data of the participants to investigate the presence of disparities in the use of DMARDs. Moreover, the lack of clinical details about the patients with JIA, including disease severity and specialty of prescribers, may have affected the interpretation of the results.

DISCLOSURES:

The study was supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and several other institutes of the National Institutes of Health, as well as the Rheumatology Research Foundation and the Juvenile Diabetes Research Foundation. No conflicts of interest were reported by the authors.

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

TOPLINE:

The use of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for treating juvenile idiopathic arthritis (JIA) rose sharply from 2001 to 2022, while the use of conventional synthetic DMARDs (csDMARDs) plummeted, with adalimumab becoming the most commonly used b/tsDMARD.

METHODOLOGY:

• Researchers performed a serial cross-sectional study using Merative MarketScan Commercial Claims and Encounters data from 2000 to 2022 to describe recent trends in DMARD use for children with JIA in the United States.
• They identified 20,258 new episodes of DMARD use among 13,696 children with JIA (median age, 14 years; 67.5% girls) who newly initiated at least one DMARD.
• Participants were required to have ≥ 365 days of continuous healthcare and pharmacy eligibility prior to the index date, defined as the date of DMARD initiation.

TAKEAWAY:

• The use of csDMARDs declined from 89.5% to 43.2% between 2001 and 2022 (P < .001 for trend), whereas the use of bDMARDs increased from 10.5% to 50.0% over the same period (P < .001).
• Methotrexate was the most commonly used DMARD throughout the study period ; however, as with other csDMARDs, its use declined from 42.1% in 2001 to 21.5% in 2022 (P < .001 ).
• Use of the tumor necrosis factor inhibitor adalimumab doubled from 7% in 2007 to 14% in 2008 and increased further up to 20.5% by 2022; adalimumab also became the most predominantly used b/tsDMARD after csDMARD monotherapy, accounting for 77.8% of prescriptions following csDMARDs in 2022.
• Even though the use of individual TNF inhibitors increased, their overall popularity fell in recent years as the use of newer b/tsDMARDs, such as ustekinumab and secukinumab, increased.

IN PRACTICE:

“These real-world treatment patterns give us insight into how selection of therapies for JIA has evolved with increasing availability of effective agents and help prepare for future studies on comparative DMARD safety and effectiveness,” the authors wrote.

SOURCE:

The study was led by Priyanka Yalamanchili, PharmD, MS, Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Rutgers University, New Brunswick, New Jersey, and was published online October 22, 2024, in Arthritis & Rheumatology.

LIMITATIONS: 

The dependence on commercial claims data may have limited the generalizability of the findings to other populations, such as those with public insurance or without insurance. The study did not have access to demographic data of the participants to investigate the presence of disparities in the use of DMARDs. Moreover, the lack of clinical details about the patients with JIA, including disease severity and specialty of prescribers, may have affected the interpretation of the results.

DISCLOSURES:

The study was supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and several other institutes of the National Institutes of Health, as well as the Rheumatology Research Foundation and the Juvenile Diabetes Research Foundation. No conflicts of interest were reported by the authors.

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

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

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

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

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

TOPLINE:

Children of mothers who had obesity or eating disorders before or during pregnancy may face higher risks for neurodevelopmental and psychiatric disorders.

METHODOLOGY:

• Researchers conducted a population-based cohort study to investigate the association of maternal eating disorders and high prepregnancy body mass index (BMI) with psychiatric disorder and neurodevelopmental diagnoses in offspring.
• They used Finnish national registers to assess all live births from 2004 through 2014, with follow-up until 2021.
• Data of 392,098 mothers (mean age, 30.15 years) and 649,956 offspring (48.86% girls) were included.
• Maternal eating disorders and prepregnancy BMI were the main exposures, with 1.60% of mothers having a history of eating disorders; 5.89% were underweight and 53.13% had obesity.
• Diagnoses of children were identified and grouped by ICD-10 codes of mental, behavioral, and neurodevelopmental disorders, mood disorders, anxiety disorders, sleep disorders, attention-deficit/hyperactivity disorder, and conduct disorders, among several others.

TAKEAWAY:

• From birth until 7-17 years of age, 16.43% of offspring were diagnosed with a neurodevelopmental or psychiatric disorder.
• Maternal eating disorders were associated with psychiatric disorders in the offspring, with the largest effect sizes observed for sleep disorders (hazard ratio [HR], 2.36) and social functioning and tic disorders (HR, 2.18; P < .001 for both).
• The offspring of mothers with severe prepregnancy obesity had a more than twofold increased risk for intellectual disabilities (HR, 2.04; 95% CI, 1.83-2.28); being underweight before pregnancy was also linked to many psychiatric disorders in offspring.
• The occurrence of adverse birth outcomes along with maternal eating disorders or high BMI further increased the risk for neurodevelopmental and psychiatric disorders in the offspring.

IN PRACTICE:

“The findings underline the risk of offspring mental illness associated with maternal eating disorders and prepregnancy BMI and suggest the need to consider these exposures clinically to help prevent offspring mental illness,” the authors wrote.

SOURCE:

This study was led by Ida A.K. Nilsson, PhD, of the Department of Molecular Medicine and Surgery at the Karolinska Institutet in Stockholm, Sweden, and was published online in JAMA Network Open.

LIMITATIONS:

A limitation of the study was the relatively short follow-up time, which restricted the inclusion of late-onset psychiatric disorder diagnoses, such as schizophrenia spectrum disorders. Paternal data and genetic information, which may have influenced the interpretation of the data, were not available. Another potential bias was that mothers with eating disorders may have been more perceptive to their child’s eating behavior, leading to greater access to care and diagnosis for these children.

DISCLOSURES:

This work was supported by the Swedish Research Council, the regional agreement on medical training and clinical research between Region Stockholm and the Karolinska Institutet, the Swedish Brain Foundation, and other sources. The authors declared no conflicts of interest.

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

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Sometime in the last year or 2 I wrote that, despite my considerable reservations, I had finally come to the conclusion that the American Medical Association’s decision to designate obesity as a disease was appropriate. My rationalization was that the disease label would open more opportunities for funding obesity treatments. However, the explosive growth and popularity of glucagon-like peptide 1 (GLP-1) agonists over the last year has had me rethinking my decision to suppress my long-held reservations about the disease designation.

So, if it’s not a disease, then what should we call it? How do we explain its surge in high-income countries that began in the 1980s? While there are still some folks who see obesity as a character flaw, I think you and I as healthcare providers have difficulty explaining the increase prevalence of obesity as either global breakdown of willpower or a widespread genetic shift as the result of burst of radiation from solar flares.

However, if we want to continue our search and finger-pointing we need to have a better definition of exactly what obesity is. If we’re going to continue calling it a disease we have done a pretty sloppy job of creating diagnostic criteria. To be honest, we aren’t doing such a hot job with “long COVID” either.

A recent article in the New York Times makes it clear that I’m not the only physician who is feeling uncomfortable with this lack of diagnostic specificity.

We know that using body mass index (BMI) as a criteria is imprecise. There are healthy individuals with elevated BMIs and there are others who are carrying an unhealthy amount of fat who have normal BMIs. And, there are individuals who have what might appear to be an excess amount of fat who are fit and healthy by other criteria.

Some investigators feel that a set of measurements that includes a waist and/or hip measurement may be a more accurate way of determining visceral adipose tissue. However, this body roundness index (BRI) currently relies on a tape measurement. Until the technique can be preformed by an inexpensive and readily available scanner, the BRI cannot be considered a practical tool for determining obesity.

Dr. Francisco Rubino, the chair of metabolic and bariatric surgery at Kings College in London, England, has been quoted as saying that, “if one defines a disease inaccurately, everything that stems from that – from diagnosis to treatment to policies – will be distorted and biased.”

Denmark has been forced to relabel obesity as a risk factor because the disease designation was stressing the financial viability of their healthcare system as more and more patients were being prescribe GLP-1 agonists, sometimes off label. A rationing strategy was resulting in suboptimal treatment of a significant portion of the obese population.

Spearheaded by Dr. Rubino, a Lancet Commission composed of physicians has tasked itself to define an “evidence-based diagnosis for obesity. Instead of relying on a single metric such as the BMI or BRI, diagnosing “clinical obesity” would involve a broad array of observations including a history, physical examination, standard laboratory and additional testing, “naming signs and symptoms, organ by organ, tissue by tissue, with plausible mechanisms for each one.” In other words, treating each patient as an individual using evidence-based criteria to make a diagnosis. While likely to be time consuming, this strategy feels like a more scientific approach. I suspect once clinical obesity is more rigorously defined it could be divided into several subtypes. For example, there would be a few conditions that were genetic; Prader-Willi syndrome being the best known.

However, I think the Lancet Commission’s strategy will find that the majority of individuals who make up this half-century global surge have become clinically obese because they have been unable to adapt to the obeseogenic forces in our society, which include diet, autocentricity, and attractive sedentary forms of entertainment, to name just three.

In some cases these unfortunate individuals are more vulnerable because there were born into an economically disadvantaged situation. In other scenarios a lack of foresight and/or political will may have left individuals with no other choice but to rely on automobiles to get around. Still others may find themselves living in a nutritional desert because all of the grocery stores have closed.

I recently encountered a descriptor in a story about the Federal Emergency Management Agency which could easily be adapted to describe this large and growing subtype of individuals with clinical obesity. “Social vulnerability” is measure of how well a community can withstand external stressors that impact human health. For example, the emergency management folks are thinking in terms of natural disaster such as hurricanes, floods, and tornadoes and are asking how well a given community can meet the challenges one would create.

But, the term social vulnerability can easily be applied to individuals living in a society in which unhealthy food is abundant, an infrastructure that discourages or outright prevents non-motorized travel, and the temptation of sedentary entertainment options is unavoidable. Fortunately, not every citizen living in an obesogenic society becomes obese. What factors have protected the non-obese individuals from these obeseogenic stressors? What are the characteristics of the unfortunate “vulnerables” living in the same society who end up being obese?

It is time to shift our focus away from a poorly defined disease model to one in which we begin looking at our society to find out why we have so many socially vulnerable individuals. The toll of obesity as it is currently defined is many order of magnitudes greater than any natural disaster. We have become communities that can no longer withstand the its obesogenic stressors many of which we have created and/or allowed to accumulate over the last century.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

I suspect you all have some experience with childhood migraine. It can mean a painful several hours for the patient, arriving often without warning, with recurrences spaced months or sometimes even years apart. It may be accompanied by vomiting, which in some cases overshadows the severity of the headache. It can result in lost days from school and ruin family activities. It can occur so infrequently that the family can’t recall accurately when the last episode happened. In some ways it is a different animal than the adult version.

Most of the pediatric patients with migraine I have seen have experienced attacks that were occurring so infrequently that the families and I seldom discussed medication as an option. Back then imipramine was the only choice. However, currently there are more than a half dozen medications and combinations that have been tried. Recently a review of 45 clinical trials of these medications was published in JAMA Network Open.

I will let you review for yourself the details of these Iranian investigators’ network meta-analysis, but the bottom line is that some medications were associated with a reduction in migraine frequency. Others were associated with headache intensity. “However, no treatments were associated with significant improvements in quality of life or reduction of the duration of migraine attacks.”

Obviously, this paper illustrates clearly that we have not yet discovered the medicinal magic bullet for pediatric migraine prophylaxis. This doesn’t surprise me. After listening to scores of families tell their migraine stories, it became apparent to me that there was often a pattern in which the child’s headache had arrived after a period of acute sleep deprivation. For example, a trip to an amusement park in which travel or excitement may have resulted in the child going to bed later and/or getting up earlier. By afternoon the child’s reserves of something (currently unknown) were depleted to a point that the headache and/or vomiting struck.

Because these episodes were often so infrequent, separated by months, that taking a history demonstrating a recurring pattern could take considerable patience on the part of the family and the provider, even for a physician like myself who believes that better sleep is the answer for everything. However, once I could convince a family of the connection between the sleep deprivation and the headaches, they could often recall other episodes in the past that substantiated my explanation.

In some cases there was no obvious history of acute sleep deprivation, or at least it was so subtle that even a history taker with a sleep obsession couldn’t detect it. However, in these cases I could usually elicit a history of chronic sleep deprivation. For example, falling asleep instantly on automobile rides, difficulty with waking in the morning, or unhealthy bedtime routines. With this underlying vulnerability of chronic sleep deprivation, a slightly more exciting or vigorous day was all that was necessary to trigger the headache.

For those of you who don’t share my contention that childhood migraine is usually the result of sleep deprivation, consider the similarity between an epileptic seizure, which can be triggered by fatigue. Both events are usually followed by a deep sleep from which the child wakes refreshed and symptom free.

I think it is interesting that this recent meta-analysis could find no benefit in the quality of life for any of the medications. The explanation may be that the child with migraine already had a somewhat diminished quality of life as a result of the sleep deprivation, either acute or chronic.

When speaking with parents of migraine sufferers, I would tell them that once the headache had started there was little I had to offer to forestall the inevitable pain and vomiting. Certainly not in the form of an oral medication. While many adults will have an aura that warns them of the headache onset, I have found that most children don’t describe an aura. It may be they simply lack the ability to express it. Occasionally an observant parent may detect pallor or a behavior change that indicates a migraine is beginning. On rare occasions a parent may be able to abort the attack by quickly getting the child to a quiet, dark, and calm environment.

Although this recent meta-analysis review of treatment options is discouraging, it may be providing a clue to effective prophylaxis. Some of the medications that decrease the frequency of the attacks may be doing so because they improve the patient’s sleep patterns. Those that decrease the intensity of the pain are probably working on pain pathway that is not specific to migraine.

Continuing a search for a prophylactic medication is a worthy goal, particularly for those patients in which their migraines are debilitating. However, based on my experience, enhanced by my bias, the safest and most effective prophylaxis results from increasing the family’s awareness of the role that sleep deprivation plays in the illness. Even when the family buys into the message and attempts to avoid situations that will tax their vulnerable children, parents will need to accept that sometimes stuff happens even though siblings and peers may be able to tolerate the situation. Spontaneous activities can converge on a day when for whatever reason the migraine-prone child is overtired and the headache and vomiting will erupt.

A lifestyle change is always preferable to a pharmacological intervention. However, that doesn’t mean it is always easy to achieve.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

I suspect you all have some experience with childhood migraine. It can mean a painful several hours for the patient, arriving often without warning, with recurrences spaced months or sometimes even years apart. It may be accompanied by vomiting, which in some cases overshadows the severity of the headache. It can result in lost days from school and ruin family activities. It can occur so infrequently that the family can’t recall accurately when the last episode happened. In some ways it is a different animal than the adult version.

Most of the pediatric patients with migraine I have seen have experienced attacks that were occurring so infrequently that the families and I seldom discussed medication as an option. Back then imipramine was the only choice. However, currently there are more than a half dozen medications and combinations that have been tried. Recently a review of 45 clinical trials of these medications was published in JAMA Network Open.

I will let you review for yourself the details of these Iranian investigators’ network meta-analysis, but the bottom line is that some medications were associated with a reduction in migraine frequency. Others were associated with headache intensity. “However, no treatments were associated with significant improvements in quality of life or reduction of the duration of migraine attacks.”

Obviously, this paper illustrates clearly that we have not yet discovered the medicinal magic bullet for pediatric migraine prophylaxis. This doesn’t surprise me. After listening to scores of families tell their migraine stories, it became apparent to me that there was often a pattern in which the child’s headache had arrived after a period of acute sleep deprivation. For example, a trip to an amusement park in which travel or excitement may have resulted in the child going to bed later and/or getting up earlier. By afternoon the child’s reserves of something (currently unknown) were depleted to a point that the headache and/or vomiting struck.

Because these episodes were often so infrequent, separated by months, that taking a history demonstrating a recurring pattern could take considerable patience on the part of the family and the provider, even for a physician like myself who believes that better sleep is the answer for everything. However, once I could convince a family of the connection between the sleep deprivation and the headaches, they could often recall other episodes in the past that substantiated my explanation.

In some cases there was no obvious history of acute sleep deprivation, or at least it was so subtle that even a history taker with a sleep obsession couldn’t detect it. However, in these cases I could usually elicit a history of chronic sleep deprivation. For example, falling asleep instantly on automobile rides, difficulty with waking in the morning, or unhealthy bedtime routines. With this underlying vulnerability of chronic sleep deprivation, a slightly more exciting or vigorous day was all that was necessary to trigger the headache.

For those of you who don’t share my contention that childhood migraine is usually the result of sleep deprivation, consider the similarity between an epileptic seizure, which can be triggered by fatigue. Both events are usually followed by a deep sleep from which the child wakes refreshed and symptom free.

I think it is interesting that this recent meta-analysis could find no benefit in the quality of life for any of the medications. The explanation may be that the child with migraine already had a somewhat diminished quality of life as a result of the sleep deprivation, either acute or chronic.

When speaking with parents of migraine sufferers, I would tell them that once the headache had started there was little I had to offer to forestall the inevitable pain and vomiting. Certainly not in the form of an oral medication. While many adults will have an aura that warns them of the headache onset, I have found that most children don’t describe an aura. It may be they simply lack the ability to express it. Occasionally an observant parent may detect pallor or a behavior change that indicates a migraine is beginning. On rare occasions a parent may be able to abort the attack by quickly getting the child to a quiet, dark, and calm environment.

Although this recent meta-analysis review of treatment options is discouraging, it may be providing a clue to effective prophylaxis. Some of the medications that decrease the frequency of the attacks may be doing so because they improve the patient’s sleep patterns. Those that decrease the intensity of the pain are probably working on pain pathway that is not specific to migraine.

Continuing a search for a prophylactic medication is a worthy goal, particularly for those patients in which their migraines are debilitating. However, based on my experience, enhanced by my bias, the safest and most effective prophylaxis results from increasing the family’s awareness of the role that sleep deprivation plays in the illness. Even when the family buys into the message and attempts to avoid situations that will tax their vulnerable children, parents will need to accept that sometimes stuff happens even though siblings and peers may be able to tolerate the situation. Spontaneous activities can converge on a day when for whatever reason the migraine-prone child is overtired and the headache and vomiting will erupt.

A lifestyle change is always preferable to a pharmacological intervention. However, that doesn’t mean it is always easy to achieve.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

I suspect you all have some experience with childhood migraine. It can mean a painful several hours for the patient, arriving often without warning, with recurrences spaced months or sometimes even years apart. It may be accompanied by vomiting, which in some cases overshadows the severity of the headache. It can result in lost days from school and ruin family activities. It can occur so infrequently that the family can’t recall accurately when the last episode happened. In some ways it is a different animal than the adult version.

Most of the pediatric patients with migraine I have seen have experienced attacks that were occurring so infrequently that the families and I seldom discussed medication as an option. Back then imipramine was the only choice. However, currently there are more than a half dozen medications and combinations that have been tried. Recently a review of 45 clinical trials of these medications was published in JAMA Network Open.

I will let you review for yourself the details of these Iranian investigators’ network meta-analysis, but the bottom line is that some medications were associated with a reduction in migraine frequency. Others were associated with headache intensity. “However, no treatments were associated with significant improvements in quality of life or reduction of the duration of migraine attacks.”

Obviously, this paper illustrates clearly that we have not yet discovered the medicinal magic bullet for pediatric migraine prophylaxis. This doesn’t surprise me. After listening to scores of families tell their migraine stories, it became apparent to me that there was often a pattern in which the child’s headache had arrived after a period of acute sleep deprivation. For example, a trip to an amusement park in which travel or excitement may have resulted in the child going to bed later and/or getting up earlier. By afternoon the child’s reserves of something (currently unknown) were depleted to a point that the headache and/or vomiting struck.

Because these episodes were often so infrequent, separated by months, that taking a history demonstrating a recurring pattern could take considerable patience on the part of the family and the provider, even for a physician like myself who believes that better sleep is the answer for everything. However, once I could convince a family of the connection between the sleep deprivation and the headaches, they could often recall other episodes in the past that substantiated my explanation.

In some cases there was no obvious history of acute sleep deprivation, or at least it was so subtle that even a history taker with a sleep obsession couldn’t detect it. However, in these cases I could usually elicit a history of chronic sleep deprivation. For example, falling asleep instantly on automobile rides, difficulty with waking in the morning, or unhealthy bedtime routines. With this underlying vulnerability of chronic sleep deprivation, a slightly more exciting or vigorous day was all that was necessary to trigger the headache.

For those of you who don’t share my contention that childhood migraine is usually the result of sleep deprivation, consider the similarity between an epileptic seizure, which can be triggered by fatigue. Both events are usually followed by a deep sleep from which the child wakes refreshed and symptom free.

I think it is interesting that this recent meta-analysis could find no benefit in the quality of life for any of the medications. The explanation may be that the child with migraine already had a somewhat diminished quality of life as a result of the sleep deprivation, either acute or chronic.

When speaking with parents of migraine sufferers, I would tell them that once the headache had started there was little I had to offer to forestall the inevitable pain and vomiting. Certainly not in the form of an oral medication. While many adults will have an aura that warns them of the headache onset, I have found that most children don’t describe an aura. It may be they simply lack the ability to express it. Occasionally an observant parent may detect pallor or a behavior change that indicates a migraine is beginning. On rare occasions a parent may be able to abort the attack by quickly getting the child to a quiet, dark, and calm environment.

Although this recent meta-analysis review of treatment options is discouraging, it may be providing a clue to effective prophylaxis. Some of the medications that decrease the frequency of the attacks may be doing so because they improve the patient’s sleep patterns. Those that decrease the intensity of the pain are probably working on pain pathway that is not specific to migraine.

Continuing a search for a prophylactic medication is a worthy goal, particularly for those patients in which their migraines are debilitating. However, based on my experience, enhanced by my bias, the safest and most effective prophylaxis results from increasing the family’s awareness of the role that sleep deprivation plays in the illness. Even when the family buys into the message and attempts to avoid situations that will tax their vulnerable children, parents will need to accept that sometimes stuff happens even though siblings and peers may be able to tolerate the situation. Spontaneous activities can converge on a day when for whatever reason the migraine-prone child is overtired and the headache and vomiting will erupt.

A lifestyle change is always preferable to a pharmacological intervention. However, that doesn’t mean it is always easy to achieve.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This transcript has been edited for clarity.

Matthew F. Watto, MD: I’m here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about rhinitis?

Paul N. Williams, MD: I’m excited. It’s always the season to talk about rhinitis.

Watto: We had a great guest for this podcast, Rhinitis and Environmental Allergies with Dr. Olajumoke Fadugba from Penn Medicine. She’s an allergist and immunologist. One of her pet peeves is when people just call everything “allergic rhinitis” because we should be calling it “chronic rhinitis,” if it’s chronic. That’s an umbrella term, and there are many buckets underneath it that people could fall into.

When you’re taking a history, you have to figure out whether it’s perennial (meaning it happens year round) because certain things can cause that. Cat dander is around all the time, so people with cats might have sinus symptoms all year. Dust mites are another one, and it’s pretty hard to avoid those. Those are some perennial allergens. 

Then there is allergic vs nonallergic rhinitis, which is something I hadn’t really put too much thought into.

Williams: I didn’t realize exactly how nuanced it got. Nonallergic rhinitis can still be seasonal because changes in temperature and humidity can trigger the rhinitis. And it matters what medications you use for what.

Watto: Here are some ways you can try to figure out if rhinitis is allergic or nonallergic. Ask the patient if they have itchy eyes and are sneezing a lot. That can be more of an allergic rhinitis, but both allergic and nonallergic rhinitis have the congestion, the rhinorrhea, so you can’t figure it out based on that alone.

Dr. Fadugba said that one clue that it might be nonallergic rhinitis is the age of onset. If the symptoms are later in onset (older age), then 30%-40% of rhinitis is nonallergic. If the patient has never had allergies and now all of a sudden they have new chronic sinus symptoms, it’s probably nonallergic rhinitis. It’s a diagnosis of exclusion.

I guess they need allergy testing?

Williams: If you want to make a definitive diagnosis, you need to rule it out. I suspect that you might be able to get away with some empirical treatment. If they get better, you can feel like a winner because getting booked in for allergy testing can be a little bit of a challenge.

Watto: The main treatment difference is that the oral antihistamines do not really seem to work for nonallergic rhinitis, but they can help with allergic rhinitis. Weirdly, the nasal antihistamines and nasal steroids do seem to work for both allergic and nonallergic rhinitis.

I don’t understand the mechanism there, but if you think someone might have nonallergic rhinitis, I wouldn’t go with the oral antihistamines as your first-line treatment. I would go with a nasal spray; you pretty much can’t go wrong with either an antihistamine or a steroid nasal spray.

Williams: We typically start with the nasal sprays. That’s kind of first-line for almost everybody, allergic or nonallergic. You’re probably going to start with an intranasal steroid, and then it’s kind of dealer’s choice what the patient can tolerate and afford. Sometimes you can get them covered by insurance, at least in my experience. 

I will say that this is one of the medications — like nicotine patches and other things — where we as doctors don’t really counsel patients on how to use it appropriately. So with our expert, we revisited the idea of the patient pointing the nasal spray laterally, toward their ear basically, and not spraying toward their brain. There should not be a slurping sound afterward, because “if you taste it, you waste it,” as the allergists and immunologists say. It’s supposed to sit up there and not be swallowed immediately. 

If your patient is sensitive to the floral flavor of some of the fluticasones (which I don’t mind so much as a user myself), then you can try mometasone or the other formulations. They are all roughly equivalent. 

Speaking of medications, which medications can cause rhinitis? Any meds we commonly use in primary care?

Williams: Apparently the combined hormonal oral contraceptives can do it. Also the phosphodiesterase 5 (PDE-5) inhibitors. Drugs that cause vasodilation can also do it. Some of the antihypertensives. I’ve seen beta-blockers and angiotensin-converting enzyme (ACE) inhibitors listed specifically, and some of the medications for benign prostatic hyperplasia (BPH). So there are a couple of medications that you can think about as a potential cause of rhinitis, although my suspicion is not going to be as high as for some of the other causes.

Watto: We mentioned medication treatments for patients who are really bothered by rhinorrhea, and maybe they are already on a steroid or an antihistamine.

You can try nasal ipratropium for people that have really prominent rhinorrhea. Dr. Fadugba said that can work well, and it’s usually taken three or four times a day. I’ve had good success prescribing it for my patients. Another one that I have never prescribed, but that Dr. Fadugba said is available over the counter, is intranasal cromolyn — a mast cell stabilizer. She said it can be beneficial.

Let’s say I had a cat allergy and I was going to visit Paul. I could use the intranasal cromolyn ahead of time to reduce rhinitis when I’m around the cats.

Paul, what about montelukast? I never know what to do with that one.

Williams: I’ve seen it prescribed as a last-ditch attempt to fix chronic rhinitis. Dr. Fadugba said she only ever prescribes it for patients who have rhinitis symptoms and asthma and never just for chronic rhinitis because it doesn’t work. And also, there have been some new black-box warnings from the US Food and Drug Administration (FDA). So unless there’s a solid indication for it, montelukast is not something you should just prescribe to try to see if it will work. That’s probably not the right approach for this.

But if the patient has challenging control asthma, and as a component, challenging nasal symptoms as well, it might be a reasonable medication to try. 

Watto: And finally, Paul, how does climate change possibly have anything to do with rhinitis?

Williams: I feel like I’m just seeing more and more of the stuff every year. I don’t know if I’m more sensitive to it or because I’m having more symptoms myself, but it turns out the prevalence actually is going up.

We’re seeing more of it in part because it’s getting hotter outside, which is in turn worsening the production of allergens and increasing the allergen exposure and the severity of the symptoms that go along with it. More people are having more severe disease because the world is changing as a result of the stuff that we do. So fix that. But also be mindful and expect to see even more of these problems as you move forward in your careers. 

Watto: Dr. Fadugba gave us so many great tips. You can listen to the full podcast episode here.

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, disclosed ties with The Curbsiders.

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

This transcript has been edited for clarity.

Matthew F. Watto, MD: I’m here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about rhinitis?

Paul N. Williams, MD: I’m excited. It’s always the season to talk about rhinitis.

Watto: We had a great guest for this podcast, Rhinitis and Environmental Allergies with Dr. Olajumoke Fadugba from Penn Medicine. She’s an allergist and immunologist. One of her pet peeves is when people just call everything “allergic rhinitis” because we should be calling it “chronic rhinitis,” if it’s chronic. That’s an umbrella term, and there are many buckets underneath it that people could fall into.

When you’re taking a history, you have to figure out whether it’s perennial (meaning it happens year round) because certain things can cause that. Cat dander is around all the time, so people with cats might have sinus symptoms all year. Dust mites are another one, and it’s pretty hard to avoid those. Those are some perennial allergens. 

Then there is allergic vs nonallergic rhinitis, which is something I hadn’t really put too much thought into.

Williams: I didn’t realize exactly how nuanced it got. Nonallergic rhinitis can still be seasonal because changes in temperature and humidity can trigger the rhinitis. And it matters what medications you use for what.

Watto: Here are some ways you can try to figure out if rhinitis is allergic or nonallergic. Ask the patient if they have itchy eyes and are sneezing a lot. That can be more of an allergic rhinitis, but both allergic and nonallergic rhinitis have the congestion, the rhinorrhea, so you can’t figure it out based on that alone.

Dr. Fadugba said that one clue that it might be nonallergic rhinitis is the age of onset. If the symptoms are later in onset (older age), then 30%-40% of rhinitis is nonallergic. If the patient has never had allergies and now all of a sudden they have new chronic sinus symptoms, it’s probably nonallergic rhinitis. It’s a diagnosis of exclusion.

I guess they need allergy testing?

Williams: If you want to make a definitive diagnosis, you need to rule it out. I suspect that you might be able to get away with some empirical treatment. If they get better, you can feel like a winner because getting booked in for allergy testing can be a little bit of a challenge.

Watto: The main treatment difference is that the oral antihistamines do not really seem to work for nonallergic rhinitis, but they can help with allergic rhinitis. Weirdly, the nasal antihistamines and nasal steroids do seem to work for both allergic and nonallergic rhinitis.

I don’t understand the mechanism there, but if you think someone might have nonallergic rhinitis, I wouldn’t go with the oral antihistamines as your first-line treatment. I would go with a nasal spray; you pretty much can’t go wrong with either an antihistamine or a steroid nasal spray.

Williams: We typically start with the nasal sprays. That’s kind of first-line for almost everybody, allergic or nonallergic. You’re probably going to start with an intranasal steroid, and then it’s kind of dealer’s choice what the patient can tolerate and afford. Sometimes you can get them covered by insurance, at least in my experience. 

I will say that this is one of the medications — like nicotine patches and other things — where we as doctors don’t really counsel patients on how to use it appropriately. So with our expert, we revisited the idea of the patient pointing the nasal spray laterally, toward their ear basically, and not spraying toward their brain. There should not be a slurping sound afterward, because “if you taste it, you waste it,” as the allergists and immunologists say. It’s supposed to sit up there and not be swallowed immediately. 

If your patient is sensitive to the floral flavor of some of the fluticasones (which I don’t mind so much as a user myself), then you can try mometasone or the other formulations. They are all roughly equivalent. 

Speaking of medications, which medications can cause rhinitis? Any meds we commonly use in primary care?

Williams: Apparently the combined hormonal oral contraceptives can do it. Also the phosphodiesterase 5 (PDE-5) inhibitors. Drugs that cause vasodilation can also do it. Some of the antihypertensives. I’ve seen beta-blockers and angiotensin-converting enzyme (ACE) inhibitors listed specifically, and some of the medications for benign prostatic hyperplasia (BPH). So there are a couple of medications that you can think about as a potential cause of rhinitis, although my suspicion is not going to be as high as for some of the other causes.

Watto: We mentioned medication treatments for patients who are really bothered by rhinorrhea, and maybe they are already on a steroid or an antihistamine.

You can try nasal ipratropium for people that have really prominent rhinorrhea. Dr. Fadugba said that can work well, and it’s usually taken three or four times a day. I’ve had good success prescribing it for my patients. Another one that I have never prescribed, but that Dr. Fadugba said is available over the counter, is intranasal cromolyn — a mast cell stabilizer. She said it can be beneficial.

Let’s say I had a cat allergy and I was going to visit Paul. I could use the intranasal cromolyn ahead of time to reduce rhinitis when I’m around the cats.

Paul, what about montelukast? I never know what to do with that one.

Williams: I’ve seen it prescribed as a last-ditch attempt to fix chronic rhinitis. Dr. Fadugba said she only ever prescribes it for patients who have rhinitis symptoms and asthma and never just for chronic rhinitis because it doesn’t work. And also, there have been some new black-box warnings from the US Food and Drug Administration (FDA). So unless there’s a solid indication for it, montelukast is not something you should just prescribe to try to see if it will work. That’s probably not the right approach for this.

But if the patient has challenging control asthma, and as a component, challenging nasal symptoms as well, it might be a reasonable medication to try. 

Watto: And finally, Paul, how does climate change possibly have anything to do with rhinitis?

Williams: I feel like I’m just seeing more and more of the stuff every year. I don’t know if I’m more sensitive to it or because I’m having more symptoms myself, but it turns out the prevalence actually is going up.

We’re seeing more of it in part because it’s getting hotter outside, which is in turn worsening the production of allergens and increasing the allergen exposure and the severity of the symptoms that go along with it. More people are having more severe disease because the world is changing as a result of the stuff that we do. So fix that. But also be mindful and expect to see even more of these problems as you move forward in your careers. 

Watto: Dr. Fadugba gave us so many great tips. You can listen to the full podcast episode here.

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, disclosed ties with The Curbsiders.

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

This transcript has been edited for clarity.

Matthew F. Watto, MD: I’m here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about rhinitis?

Paul N. Williams, MD: I’m excited. It’s always the season to talk about rhinitis.

Watto: We had a great guest for this podcast, Rhinitis and Environmental Allergies with Dr. Olajumoke Fadugba from Penn Medicine. She’s an allergist and immunologist. One of her pet peeves is when people just call everything “allergic rhinitis” because we should be calling it “chronic rhinitis,” if it’s chronic. That’s an umbrella term, and there are many buckets underneath it that people could fall into.

When you’re taking a history, you have to figure out whether it’s perennial (meaning it happens year round) because certain things can cause that. Cat dander is around all the time, so people with cats might have sinus symptoms all year. Dust mites are another one, and it’s pretty hard to avoid those. Those are some perennial allergens. 

Then there is allergic vs nonallergic rhinitis, which is something I hadn’t really put too much thought into.

Williams: I didn’t realize exactly how nuanced it got. Nonallergic rhinitis can still be seasonal because changes in temperature and humidity can trigger the rhinitis. And it matters what medications you use for what.

Watto: Here are some ways you can try to figure out if rhinitis is allergic or nonallergic. Ask the patient if they have itchy eyes and are sneezing a lot. That can be more of an allergic rhinitis, but both allergic and nonallergic rhinitis have the congestion, the rhinorrhea, so you can’t figure it out based on that alone.

Dr. Fadugba said that one clue that it might be nonallergic rhinitis is the age of onset. If the symptoms are later in onset (older age), then 30%-40% of rhinitis is nonallergic. If the patient has never had allergies and now all of a sudden they have new chronic sinus symptoms, it’s probably nonallergic rhinitis. It’s a diagnosis of exclusion.

I guess they need allergy testing?

Williams: If you want to make a definitive diagnosis, you need to rule it out. I suspect that you might be able to get away with some empirical treatment. If they get better, you can feel like a winner because getting booked in for allergy testing can be a little bit of a challenge.

Watto: The main treatment difference is that the oral antihistamines do not really seem to work for nonallergic rhinitis, but they can help with allergic rhinitis. Weirdly, the nasal antihistamines and nasal steroids do seem to work for both allergic and nonallergic rhinitis.

I don’t understand the mechanism there, but if you think someone might have nonallergic rhinitis, I wouldn’t go with the oral antihistamines as your first-line treatment. I would go with a nasal spray; you pretty much can’t go wrong with either an antihistamine or a steroid nasal spray.

Williams: We typically start with the nasal sprays. That’s kind of first-line for almost everybody, allergic or nonallergic. You’re probably going to start with an intranasal steroid, and then it’s kind of dealer’s choice what the patient can tolerate and afford. Sometimes you can get them covered by insurance, at least in my experience. 

I will say that this is one of the medications — like nicotine patches and other things — where we as doctors don’t really counsel patients on how to use it appropriately. So with our expert, we revisited the idea of the patient pointing the nasal spray laterally, toward their ear basically, and not spraying toward their brain. There should not be a slurping sound afterward, because “if you taste it, you waste it,” as the allergists and immunologists say. It’s supposed to sit up there and not be swallowed immediately. 

If your patient is sensitive to the floral flavor of some of the fluticasones (which I don’t mind so much as a user myself), then you can try mometasone or the other formulations. They are all roughly equivalent. 

Speaking of medications, which medications can cause rhinitis? Any meds we commonly use in primary care?

Williams: Apparently the combined hormonal oral contraceptives can do it. Also the phosphodiesterase 5 (PDE-5) inhibitors. Drugs that cause vasodilation can also do it. Some of the antihypertensives. I’ve seen beta-blockers and angiotensin-converting enzyme (ACE) inhibitors listed specifically, and some of the medications for benign prostatic hyperplasia (BPH). So there are a couple of medications that you can think about as a potential cause of rhinitis, although my suspicion is not going to be as high as for some of the other causes.

Watto: We mentioned medication treatments for patients who are really bothered by rhinorrhea, and maybe they are already on a steroid or an antihistamine.

You can try nasal ipratropium for people that have really prominent rhinorrhea. Dr. Fadugba said that can work well, and it’s usually taken three or four times a day. I’ve had good success prescribing it for my patients. Another one that I have never prescribed, but that Dr. Fadugba said is available over the counter, is intranasal cromolyn — a mast cell stabilizer. She said it can be beneficial.

Let’s say I had a cat allergy and I was going to visit Paul. I could use the intranasal cromolyn ahead of time to reduce rhinitis when I’m around the cats.

Paul, what about montelukast? I never know what to do with that one.

Williams: I’ve seen it prescribed as a last-ditch attempt to fix chronic rhinitis. Dr. Fadugba said she only ever prescribes it for patients who have rhinitis symptoms and asthma and never just for chronic rhinitis because it doesn’t work. And also, there have been some new black-box warnings from the US Food and Drug Administration (FDA). So unless there’s a solid indication for it, montelukast is not something you should just prescribe to try to see if it will work. That’s probably not the right approach for this.

But if the patient has challenging control asthma, and as a component, challenging nasal symptoms as well, it might be a reasonable medication to try. 

Watto: And finally, Paul, how does climate change possibly have anything to do with rhinitis?

Williams: I feel like I’m just seeing more and more of the stuff every year. I don’t know if I’m more sensitive to it or because I’m having more symptoms myself, but it turns out the prevalence actually is going up.

We’re seeing more of it in part because it’s getting hotter outside, which is in turn worsening the production of allergens and increasing the allergen exposure and the severity of the symptoms that go along with it. More people are having more severe disease because the world is changing as a result of the stuff that we do. So fix that. But also be mindful and expect to see even more of these problems as you move forward in your careers. 

Watto: Dr. Fadugba gave us so many great tips. You can listen to the full podcast episode here.

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, disclosed ties with The Curbsiders.

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

TOPLINE:

Compared with six cycles, three cycles of chemotherapy for high-risk retinoblastoma showed noninferior 5-year disease-free survival (DFS). The three-cycle regimen also resulted in fewer adverse events and lower costs.

METHODOLOGY:

• The introduction of chemotherapy has increased survival rates for patients with retinoblastoma, but the optimal number of postoperative adjuvant cycles remains unclear due to scant randomized clinical trial data for high-risk patients.
• In the new trial, participants at two premier eye centers in China were randomly assigned to receive either three (n = 94) or six (n = 93) cycles of carboplatin, etoposide, and vincristine (CEV) chemotherapy after enucleation.
• The primary endpoint was 5-year DFS, and the secondary endpoints were overall survival, safety, economic burden, and quality of life.
• Patients were followed up every 3 months for the first 2 years and then every 6 months thereafter, with a median follow-up of 79 months.
• Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).

TAKEAWAY:

• The 5-year DFS rates were 90.4% and 89.2% for the three- and six-cycle groups, respectively, meeting the noninferiority criterion (P = .003).
• The six-cycle group experienced a higher frequency of adverse events, including neutropenia, anemia, and nausea, than the three-cycle group.
• The quality-of-life scores were higher in the three-cycle group, particularly in physical, emotional, and social functioning parameters.
• The total, direct, and indirect costs were significantly lower in the three-cycle group than in the six-cycle group.

IN PRACTICE:

“A three-cycle CEV regimen demonstrated noninferiority, compared with a six-cycle approach, and was and proved to be an efficacious adjuvant chemotherapy regimen for individuals diagnosed with pathologically high-risk retinoblastoma,” the authors of the study wrote.

In an accompanying editorial, Ning Li, MD, and colleagues wrote that the findings “could lead to changes in clinical practice, reducing treatment burden and costs without compromising patient outcomes.”
 

SOURCE:

This study was led by Huijing Ye, MD, PhD, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University in Guangzhou, China. Both the study and editorial were published online in JAMA.

LIMITATIONS: 

The open-label design of the study might introduce bias, although an independent, blinded committee evaluated the clinical outcomes. The 12% noninferiority margin was notably substantial, considering the rarity of retinoblastoma and the wide range of survival rates. The criteria for adjuvant therapy, especially regarding choroidal invasion, were debatable and required further follow-up to clarify the prognosis related to various pathologic features.

DISCLOSURES:

This study was supported by the Sun Yat-Sen University Clinical Research 5010 Program and the Shanghai Committee of Science and Technology. No relevant conflict of interest was disclosed by the authors of the paper or the editorial.

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

TOPLINE:

Compared with six cycles, three cycles of chemotherapy for high-risk retinoblastoma showed noninferior 5-year disease-free survival (DFS). The three-cycle regimen also resulted in fewer adverse events and lower costs.

METHODOLOGY:

• The introduction of chemotherapy has increased survival rates for patients with retinoblastoma, but the optimal number of postoperative adjuvant cycles remains unclear due to scant randomized clinical trial data for high-risk patients.
• In the new trial, participants at two premier eye centers in China were randomly assigned to receive either three (n = 94) or six (n = 93) cycles of carboplatin, etoposide, and vincristine (CEV) chemotherapy after enucleation.
• The primary endpoint was 5-year DFS, and the secondary endpoints were overall survival, safety, economic burden, and quality of life.
• Patients were followed up every 3 months for the first 2 years and then every 6 months thereafter, with a median follow-up of 79 months.
• Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).

TAKEAWAY:

• The 5-year DFS rates were 90.4% and 89.2% for the three- and six-cycle groups, respectively, meeting the noninferiority criterion (P = .003).
• The six-cycle group experienced a higher frequency of adverse events, including neutropenia, anemia, and nausea, than the three-cycle group.
• The quality-of-life scores were higher in the three-cycle group, particularly in physical, emotional, and social functioning parameters.
• The total, direct, and indirect costs were significantly lower in the three-cycle group than in the six-cycle group.

IN PRACTICE:

“A three-cycle CEV regimen demonstrated noninferiority, compared with a six-cycle approach, and was and proved to be an efficacious adjuvant chemotherapy regimen for individuals diagnosed with pathologically high-risk retinoblastoma,” the authors of the study wrote.

In an accompanying editorial, Ning Li, MD, and colleagues wrote that the findings “could lead to changes in clinical practice, reducing treatment burden and costs without compromising patient outcomes.”
 

SOURCE:

This study was led by Huijing Ye, MD, PhD, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University in Guangzhou, China. Both the study and editorial were published online in JAMA.

LIMITATIONS: 

The open-label design of the study might introduce bias, although an independent, blinded committee evaluated the clinical outcomes. The 12% noninferiority margin was notably substantial, considering the rarity of retinoblastoma and the wide range of survival rates. The criteria for adjuvant therapy, especially regarding choroidal invasion, were debatable and required further follow-up to clarify the prognosis related to various pathologic features.

DISCLOSURES:

This study was supported by the Sun Yat-Sen University Clinical Research 5010 Program and the Shanghai Committee of Science and Technology. No relevant conflict of interest was disclosed by the authors of the paper or the editorial.

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

TOPLINE:

Compared with six cycles, three cycles of chemotherapy for high-risk retinoblastoma showed noninferior 5-year disease-free survival (DFS). The three-cycle regimen also resulted in fewer adverse events and lower costs.

METHODOLOGY:

• The introduction of chemotherapy has increased survival rates for patients with retinoblastoma, but the optimal number of postoperative adjuvant cycles remains unclear due to scant randomized clinical trial data for high-risk patients.
• In the new trial, participants at two premier eye centers in China were randomly assigned to receive either three (n = 94) or six (n = 93) cycles of carboplatin, etoposide, and vincristine (CEV) chemotherapy after enucleation.
• The primary endpoint was 5-year DFS, and the secondary endpoints were overall survival, safety, economic burden, and quality of life.
• Patients were followed up every 3 months for the first 2 years and then every 6 months thereafter, with a median follow-up of 79 months.
• Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).

TAKEAWAY:

• The 5-year DFS rates were 90.4% and 89.2% for the three- and six-cycle groups, respectively, meeting the noninferiority criterion (P = .003).
• The six-cycle group experienced a higher frequency of adverse events, including neutropenia, anemia, and nausea, than the three-cycle group.
• The quality-of-life scores were higher in the three-cycle group, particularly in physical, emotional, and social functioning parameters.
• The total, direct, and indirect costs were significantly lower in the three-cycle group than in the six-cycle group.

IN PRACTICE:

“A three-cycle CEV regimen demonstrated noninferiority, compared with a six-cycle approach, and was and proved to be an efficacious adjuvant chemotherapy regimen for individuals diagnosed with pathologically high-risk retinoblastoma,” the authors of the study wrote.

In an accompanying editorial, Ning Li, MD, and colleagues wrote that the findings “could lead to changes in clinical practice, reducing treatment burden and costs without compromising patient outcomes.”
 

SOURCE:

This study was led by Huijing Ye, MD, PhD, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University in Guangzhou, China. Both the study and editorial were published online in JAMA.

LIMITATIONS: 

The open-label design of the study might introduce bias, although an independent, blinded committee evaluated the clinical outcomes. The 12% noninferiority margin was notably substantial, considering the rarity of retinoblastoma and the wide range of survival rates. The criteria for adjuvant therapy, especially regarding choroidal invasion, were debatable and required further follow-up to clarify the prognosis related to various pathologic features.

DISCLOSURES:

This study was supported by the Sun Yat-Sen University Clinical Research 5010 Program and the Shanghai Committee of Science and Technology. No relevant conflict of interest was disclosed by the authors of the paper or the editorial.

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

TOPLINE:

Long-term treatment with upadacitinib in adolescents with moderate to severe atopic dermatitis (AD) demonstrated sustained efficacy and an acceptable safety profile through 76 weeks across three phase 3 trials.

METHODOLOGY:

• Researchers conducted three double-blind, placebo-controlled phase 3 randomized clinical trials (Measure Up 1, Measure Up 2, and AD Up) involving 542 adolescents aged 12-17 years with moderate to severe AD.
• Participants were randomized to receive the oral Janus kinase inhibitor upadacitinib (15 mg or 30 mg once daily) or placebo, with or without topical corticosteroids, for 16 weeks, followed by rerandomization of patients in the placebo group to upadacitinib for up to 76 weeks.
• Study endpoints were at least a 75%, 90%, or 100% reduction in the Eczema Area and Severity Index (EASI-75, EASI-90, and EASI-100, respectively), Validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, and a ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS).
• Adverse events were monitored, including serious infections, herpes zoster, and creatine kinase elevation.

TAKEAWAY:

• Among those who continued treatment on upadacitinib, 15 mg and 30 mg, EASI-75 response rates were maintained or improved through week 76 in all three studies. Patients who switched from placebo to upadacitinib also experienced improvements in EASI-75 through week 76.
• The proportion of patients who achieved EASI-90 and EASI-100 responses increased, and in general, were maintained from week 16 through week 76 in all three studies; the proportion was numerically higher among patients on 30 mg for all three studies.
• The proportion of adolescents achieving vIGA-AD score of 0 or 1 and WP-NRS improvement of ≥ 4 points was sustained or improved through 76 weeks.
• Serious infections were reported in five patients or fewer in each treatment group for all three studies. All opportunistic infections were eczema herpeticum; most cases were not serious, or were mild or moderate, and in general, did not require stopping treatment.

IN PRACTICE:

“These results through 76 weeks demonstrated that upadacitinib, with a favorable benefit-risk profile, was an effective long-term treatment option for adolescents with moderate to severe AD,” the authors wrote.

SOURCE:

The study was led by Amy S. Paller, MD, professor and chair of dermatology, Northwestern University, Chicago, and was published online on October 23 in JAMA Dermatology.

LIMITATIONS: 

The study limitations included a small sample size, and the findings did not extend to patients under 12 years or those weighing < 40 kg.

DISCLOSURES:

This study was supported by AbbVie. Paller received grants and personal fees from pharmaceutical companies including AbbVie during the conduct of the study. Several authors reported financial ties with various sources, including AbbVie.

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

TOPLINE:

Long-term treatment with upadacitinib in adolescents with moderate to severe atopic dermatitis (AD) demonstrated sustained efficacy and an acceptable safety profile through 76 weeks across three phase 3 trials.

METHODOLOGY:

• Researchers conducted three double-blind, placebo-controlled phase 3 randomized clinical trials (Measure Up 1, Measure Up 2, and AD Up) involving 542 adolescents aged 12-17 years with moderate to severe AD.
• Participants were randomized to receive the oral Janus kinase inhibitor upadacitinib (15 mg or 30 mg once daily) or placebo, with or without topical corticosteroids, for 16 weeks, followed by rerandomization of patients in the placebo group to upadacitinib for up to 76 weeks.
• Study endpoints were at least a 75%, 90%, or 100% reduction in the Eczema Area and Severity Index (EASI-75, EASI-90, and EASI-100, respectively), Validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, and a ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS).
• Adverse events were monitored, including serious infections, herpes zoster, and creatine kinase elevation.

TAKEAWAY:

• Among those who continued treatment on upadacitinib, 15 mg and 30 mg, EASI-75 response rates were maintained or improved through week 76 in all three studies. Patients who switched from placebo to upadacitinib also experienced improvements in EASI-75 through week 76.
• The proportion of patients who achieved EASI-90 and EASI-100 responses increased, and in general, were maintained from week 16 through week 76 in all three studies; the proportion was numerically higher among patients on 30 mg for all three studies.
• The proportion of adolescents achieving vIGA-AD score of 0 or 1 and WP-NRS improvement of ≥ 4 points was sustained or improved through 76 weeks.
• Serious infections were reported in five patients or fewer in each treatment group for all three studies. All opportunistic infections were eczema herpeticum; most cases were not serious, or were mild or moderate, and in general, did not require stopping treatment.

IN PRACTICE:

“These results through 76 weeks demonstrated that upadacitinib, with a favorable benefit-risk profile, was an effective long-term treatment option for adolescents with moderate to severe AD,” the authors wrote.

SOURCE:

The study was led by Amy S. Paller, MD, professor and chair of dermatology, Northwestern University, Chicago, and was published online on October 23 in JAMA Dermatology.

LIMITATIONS: 

The study limitations included a small sample size, and the findings did not extend to patients under 12 years or those weighing < 40 kg.

DISCLOSURES:

This study was supported by AbbVie. Paller received grants and personal fees from pharmaceutical companies including AbbVie during the conduct of the study. Several authors reported financial ties with various sources, including AbbVie.

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

TOPLINE:

Long-term treatment with upadacitinib in adolescents with moderate to severe atopic dermatitis (AD) demonstrated sustained efficacy and an acceptable safety profile through 76 weeks across three phase 3 trials.

METHODOLOGY:

• Researchers conducted three double-blind, placebo-controlled phase 3 randomized clinical trials (Measure Up 1, Measure Up 2, and AD Up) involving 542 adolescents aged 12-17 years with moderate to severe AD.
• Participants were randomized to receive the oral Janus kinase inhibitor upadacitinib (15 mg or 30 mg once daily) or placebo, with or without topical corticosteroids, for 16 weeks, followed by rerandomization of patients in the placebo group to upadacitinib for up to 76 weeks.
• Study endpoints were at least a 75%, 90%, or 100% reduction in the Eczema Area and Severity Index (EASI-75, EASI-90, and EASI-100, respectively), Validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, and a ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS).
• Adverse events were monitored, including serious infections, herpes zoster, and creatine kinase elevation.

TAKEAWAY:

• Among those who continued treatment on upadacitinib, 15 mg and 30 mg, EASI-75 response rates were maintained or improved through week 76 in all three studies. Patients who switched from placebo to upadacitinib also experienced improvements in EASI-75 through week 76.
• The proportion of patients who achieved EASI-90 and EASI-100 responses increased, and in general, were maintained from week 16 through week 76 in all three studies; the proportion was numerically higher among patients on 30 mg for all three studies.
• The proportion of adolescents achieving vIGA-AD score of 0 or 1 and WP-NRS improvement of ≥ 4 points was sustained or improved through 76 weeks.
• Serious infections were reported in five patients or fewer in each treatment group for all three studies. All opportunistic infections were eczema herpeticum; most cases were not serious, or were mild or moderate, and in general, did not require stopping treatment.

IN PRACTICE:

“These results through 76 weeks demonstrated that upadacitinib, with a favorable benefit-risk profile, was an effective long-term treatment option for adolescents with moderate to severe AD,” the authors wrote.

SOURCE:

The study was led by Amy S. Paller, MD, professor and chair of dermatology, Northwestern University, Chicago, and was published online on October 23 in JAMA Dermatology.

LIMITATIONS: 

The study limitations included a small sample size, and the findings did not extend to patients under 12 years or those weighing < 40 kg.

DISCLOSURES:

This study was supported by AbbVie. Paller received grants and personal fees from pharmaceutical companies including AbbVie during the conduct of the study. Several authors reported financial ties with various sources, including AbbVie.

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

HUNTINGTON BEACH, CALIFORNIA — Dermatologists who believe they have little to offer LGBTQ children and adolescents beyond routine care, Markus Boos, MD, PhD, urges them to consider the potential impact they can have on these patients.

“Sometimes in dermatology we might say, ‘This gender care stuff, that’s really for pediatricians and primary care doctors,’ ” Boos, a pediatric dermatologist at Seattle Children’s Hospital, Seattle, said at the annual meeting of the Pacific Dermatologic Association. However, he added, “gender-affirming care happens not only with medications but with communication, curiosity, and respect.” For instance, an LGBTQ patient who is being treated with isotretinoin for acne is seen once a month by a dermatologist, which is probably more frequent than seeing their primary care physician, he said. “Every time you see that child, you can make them feel seen. You can respect them. You can let them know that you care about them. Hopefully then they understand what it feels like to get good care from a provider and then will not settle for poor care from someone else.”

According to Gallup polling, the proportion of people in the United States who identify as non-cisgender or nonheterosexual increased from 3.5% in 2012 to 7% in 2021. “The estimation is that 2.5%-3.5% of all teenagers identify as gay or bisexual, and another 1% identify as transgender, though some studies estimate the percentage of gender diverse youth to be as high as 9.2%,” said Boos.

Dr. Boos

He discussed several barriers to dermatologic care for LGBTQ youth, including availability. “There are only about 400 practicing pediatric dermatologists in the US, so there’s not a lot of pediatric dermatology care to go around for any child,” Boos said. “My plea to general dermatologists who see adolescents and teenagers: You can care for LGBTQ adolescents; they need your help.”

Accessibility is also an issue. For example, his clinic is in a wealthy and somewhat isolated area of Seattle, “which makes it hard for some patients to access our services because they may have to drive from far away or take multiple modes of public transportation to see us,” explained Boos, who came out as gay about 10 years ago after beginning his practice in Seattle. “Time matters, too. Children are in school. They don’t necessarily want to take time off to go to the doctor’s office. We want to make sure we have services at different times of day, including evenings or weekends if possible.”

Another potential barrier to care for this patient population is acceptability. “I can say that I welcome any patient to my practice, but if I’m not humble and informed about their concerns, especially queer or trans kids, if they feel that I’m not respecting them, that’s going to be a huge problem,” Boos said. “They won’t view that care as acceptable, and they’re not going to come back if they feel like I’m not looking out for their best interests.”

In a large cross-sectional study of patients with chronic inflammatory skin diseases published in 2023, sexual and gender minority (SGM) individuals were significantly more likely than non-SGM individuals to delay specialist care including dermatologic care (adjusted odds ratio [AOR], 1.23), mental health care (AOR, 1.62), and filing a prescription (AOR, 1.30) because of cost. The barriers for SGM patients were transportation issues, not having a healthcare practitioner (HCP) from the same racial or ethnic background, “and they were more likely to report not always being treated with respect by HCPs,” said Boos, who was not involved with the study. “SGM patients of minoritized racial identities such as Black, Hispanic, and Latino were also more likely to experience barriers to care.”

Boos offered several tips for improving the dermatologic care of LGBTQ youth:

Use inclusive language and follow your patient’s lead. “There are many ways that people identify, both with respect to their sexual orientation and their gender identity,” he said. “We often think that a person is either gay or straight, or cisgender or transgender. There are many folks who reject these binaries and may view their gender identity or sexual orientation outside of these descriptors. You can be bisexual. You can be asexual.” He also emphasized that sexual orientation is different from sexual behavior.

Be deliberate about your phrasing. Boos said he strives to make new patients feel comfortable by asking them such questions as what pronouns they use, how he should address them, and whether they have a partner or are in a relationship. “Then, in general, just follow your patient’s lead,” Boos said. “If they’re referring to their partner in a certain way or to themselves with certain pronouns, go along with it. When in doubt, just ask. And if you make a mistake like using the wrong pronouns or name of a patient, the best thing to do is immediately apologize and try your best not to repeat that error.”

When asking about sexual practices, don’t make assumptions. Boos recommends a 2019 article on dermatologic care of LGBT persons, published in the Journal of the American Academy of Dermatology, which includes specific examples of how to elicit a sexual history from adults and teens. One of the recommendations is “to be very direct, say, ‘This may feel uncomfortable, but I have to ask you these direct questions about what you’re doing sexually because I need to understand if you’re at risk for things like sexually transmitted infections,’ ” Boos said. “It’s also important to use terminology that our patients know. If I ask someone if they’ve had sex before, they usually understand that as penile-vaginal intercourse, but it’s also important to understand if they have oral or anal sex. But if you ask, ‘Have you had insertive anal sex?’ they may not know what that means as opposed to receptive anal sex. Instead, you might ask, ‘Are you a top or a bottom?’ which are more commonly used and understood terms in the queer community. It may feel really uncomfortable to use that kind of language, but we want to make sure patients understand what we’re asking them so we can take the best possible care of them.”

Pay attention to the details. One way to demonstrate inclusivity in your practice includes collecting pronoun and sexual orientation information for the electronic medical record so your entire staff can use proper pronouns for the patient. “Also, acknowledge that for queer folks, family can mean more than just biological family,” Boos added. “I do not buy into the stereotype that all queer kids are ostracized from their families and not loved by their families, but it is true that they are at risk for those experiences. So, sometimes a member of the patient’s ‘chosen family’ accompanies them on their visit.”

Privacy is also key. “You never know who else is in the room when you’re on a telehealth call, so you need to address that before you ask about personal things,” Boos said. “One sticking point that can also come up is that parents often fill out their child’s patient demographic form, which may not tell the real story. I typically start to have confidential time without parents and may take a sexual history as early as 12 or 13 years of age if it’s a patient that I’m seeing for an extended period or if I’m worried about a skin finding that might suggest an STI.”

He highlighted the unique opportunity dermatologists have to transform the healthcare landscape for LGBTQ children and adolescents. “It’s about extending yourself to nurture the growth of another person,” Boos said. “This can feel challenging, but you want to see each person for who they are and help get them to where they want to go. That’s what we went into medicine for, right? We want to care about people.”

Boos had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

HUNTINGTON BEACH, CALIFORNIA — Dermatologists who believe they have little to offer LGBTQ children and adolescents beyond routine care, Markus Boos, MD, PhD, urges them to consider the potential impact they can have on these patients.

“Sometimes in dermatology we might say, ‘This gender care stuff, that’s really for pediatricians and primary care doctors,’ ” Boos, a pediatric dermatologist at Seattle Children’s Hospital, Seattle, said at the annual meeting of the Pacific Dermatologic Association. However, he added, “gender-affirming care happens not only with medications but with communication, curiosity, and respect.” For instance, an LGBTQ patient who is being treated with isotretinoin for acne is seen once a month by a dermatologist, which is probably more frequent than seeing their primary care physician, he said. “Every time you see that child, you can make them feel seen. You can respect them. You can let them know that you care about them. Hopefully then they understand what it feels like to get good care from a provider and then will not settle for poor care from someone else.”

According to Gallup polling, the proportion of people in the United States who identify as non-cisgender or nonheterosexual increased from 3.5% in 2012 to 7% in 2021. “The estimation is that 2.5%-3.5% of all teenagers identify as gay or bisexual, and another 1% identify as transgender, though some studies estimate the percentage of gender diverse youth to be as high as 9.2%,” said Boos.

Dr. Boos

He discussed several barriers to dermatologic care for LGBTQ youth, including availability. “There are only about 400 practicing pediatric dermatologists in the US, so there’s not a lot of pediatric dermatology care to go around for any child,” Boos said. “My plea to general dermatologists who see adolescents and teenagers: You can care for LGBTQ adolescents; they need your help.”

Accessibility is also an issue. For example, his clinic is in a wealthy and somewhat isolated area of Seattle, “which makes it hard for some patients to access our services because they may have to drive from far away or take multiple modes of public transportation to see us,” explained Boos, who came out as gay about 10 years ago after beginning his practice in Seattle. “Time matters, too. Children are in school. They don’t necessarily want to take time off to go to the doctor’s office. We want to make sure we have services at different times of day, including evenings or weekends if possible.”

Another potential barrier to care for this patient population is acceptability. “I can say that I welcome any patient to my practice, but if I’m not humble and informed about their concerns, especially queer or trans kids, if they feel that I’m not respecting them, that’s going to be a huge problem,” Boos said. “They won’t view that care as acceptable, and they’re not going to come back if they feel like I’m not looking out for their best interests.”

In a large cross-sectional study of patients with chronic inflammatory skin diseases published in 2023, sexual and gender minority (SGM) individuals were significantly more likely than non-SGM individuals to delay specialist care including dermatologic care (adjusted odds ratio [AOR], 1.23), mental health care (AOR, 1.62), and filing a prescription (AOR, 1.30) because of cost. The barriers for SGM patients were transportation issues, not having a healthcare practitioner (HCP) from the same racial or ethnic background, “and they were more likely to report not always being treated with respect by HCPs,” said Boos, who was not involved with the study. “SGM patients of minoritized racial identities such as Black, Hispanic, and Latino were also more likely to experience barriers to care.”

Boos offered several tips for improving the dermatologic care of LGBTQ youth:

Use inclusive language and follow your patient’s lead. “There are many ways that people identify, both with respect to their sexual orientation and their gender identity,” he said. “We often think that a person is either gay or straight, or cisgender or transgender. There are many folks who reject these binaries and may view their gender identity or sexual orientation outside of these descriptors. You can be bisexual. You can be asexual.” He also emphasized that sexual orientation is different from sexual behavior.

Be deliberate about your phrasing. Boos said he strives to make new patients feel comfortable by asking them such questions as what pronouns they use, how he should address them, and whether they have a partner or are in a relationship. “Then, in general, just follow your patient’s lead,” Boos said. “If they’re referring to their partner in a certain way or to themselves with certain pronouns, go along with it. When in doubt, just ask. And if you make a mistake like using the wrong pronouns or name of a patient, the best thing to do is immediately apologize and try your best not to repeat that error.”

When asking about sexual practices, don’t make assumptions. Boos recommends a 2019 article on dermatologic care of LGBT persons, published in the Journal of the American Academy of Dermatology, which includes specific examples of how to elicit a sexual history from adults and teens. One of the recommendations is “to be very direct, say, ‘This may feel uncomfortable, but I have to ask you these direct questions about what you’re doing sexually because I need to understand if you’re at risk for things like sexually transmitted infections,’ ” Boos said. “It’s also important to use terminology that our patients know. If I ask someone if they’ve had sex before, they usually understand that as penile-vaginal intercourse, but it’s also important to understand if they have oral or anal sex. But if you ask, ‘Have you had insertive anal sex?’ they may not know what that means as opposed to receptive anal sex. Instead, you might ask, ‘Are you a top or a bottom?’ which are more commonly used and understood terms in the queer community. It may feel really uncomfortable to use that kind of language, but we want to make sure patients understand what we’re asking them so we can take the best possible care of them.”

Pay attention to the details. One way to demonstrate inclusivity in your practice includes collecting pronoun and sexual orientation information for the electronic medical record so your entire staff can use proper pronouns for the patient. “Also, acknowledge that for queer folks, family can mean more than just biological family,” Boos added. “I do not buy into the stereotype that all queer kids are ostracized from their families and not loved by their families, but it is true that they are at risk for those experiences. So, sometimes a member of the patient’s ‘chosen family’ accompanies them on their visit.”

Privacy is also key. “You never know who else is in the room when you’re on a telehealth call, so you need to address that before you ask about personal things,” Boos said. “One sticking point that can also come up is that parents often fill out their child’s patient demographic form, which may not tell the real story. I typically start to have confidential time without parents and may take a sexual history as early as 12 or 13 years of age if it’s a patient that I’m seeing for an extended period or if I’m worried about a skin finding that might suggest an STI.”

He highlighted the unique opportunity dermatologists have to transform the healthcare landscape for LGBTQ children and adolescents. “It’s about extending yourself to nurture the growth of another person,” Boos said. “This can feel challenging, but you want to see each person for who they are and help get them to where they want to go. That’s what we went into medicine for, right? We want to care about people.”

Boos had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

HUNTINGTON BEACH, CALIFORNIA — Dermatologists who believe they have little to offer LGBTQ children and adolescents beyond routine care, Markus Boos, MD, PhD, urges them to consider the potential impact they can have on these patients.

“Sometimes in dermatology we might say, ‘This gender care stuff, that’s really for pediatricians and primary care doctors,’ ” Boos, a pediatric dermatologist at Seattle Children’s Hospital, Seattle, said at the annual meeting of the Pacific Dermatologic Association. However, he added, “gender-affirming care happens not only with medications but with communication, curiosity, and respect.” For instance, an LGBTQ patient who is being treated with isotretinoin for acne is seen once a month by a dermatologist, which is probably more frequent than seeing their primary care physician, he said. “Every time you see that child, you can make them feel seen. You can respect them. You can let them know that you care about them. Hopefully then they understand what it feels like to get good care from a provider and then will not settle for poor care from someone else.”

According to Gallup polling, the proportion of people in the United States who identify as non-cisgender or nonheterosexual increased from 3.5% in 2012 to 7% in 2021. “The estimation is that 2.5%-3.5% of all teenagers identify as gay or bisexual, and another 1% identify as transgender, though some studies estimate the percentage of gender diverse youth to be as high as 9.2%,” said Boos.

Dr. Boos

He discussed several barriers to dermatologic care for LGBTQ youth, including availability. “There are only about 400 practicing pediatric dermatologists in the US, so there’s not a lot of pediatric dermatology care to go around for any child,” Boos said. “My plea to general dermatologists who see adolescents and teenagers: You can care for LGBTQ adolescents; they need your help.”

Accessibility is also an issue. For example, his clinic is in a wealthy and somewhat isolated area of Seattle, “which makes it hard for some patients to access our services because they may have to drive from far away or take multiple modes of public transportation to see us,” explained Boos, who came out as gay about 10 years ago after beginning his practice in Seattle. “Time matters, too. Children are in school. They don’t necessarily want to take time off to go to the doctor’s office. We want to make sure we have services at different times of day, including evenings or weekends if possible.”

Another potential barrier to care for this patient population is acceptability. “I can say that I welcome any patient to my practice, but if I’m not humble and informed about their concerns, especially queer or trans kids, if they feel that I’m not respecting them, that’s going to be a huge problem,” Boos said. “They won’t view that care as acceptable, and they’re not going to come back if they feel like I’m not looking out for their best interests.”

In a large cross-sectional study of patients with chronic inflammatory skin diseases published in 2023, sexual and gender minority (SGM) individuals were significantly more likely than non-SGM individuals to delay specialist care including dermatologic care (adjusted odds ratio [AOR], 1.23), mental health care (AOR, 1.62), and filing a prescription (AOR, 1.30) because of cost. The barriers for SGM patients were transportation issues, not having a healthcare practitioner (HCP) from the same racial or ethnic background, “and they were more likely to report not always being treated with respect by HCPs,” said Boos, who was not involved with the study. “SGM patients of minoritized racial identities such as Black, Hispanic, and Latino were also more likely to experience barriers to care.”

Boos offered several tips for improving the dermatologic care of LGBTQ youth:

Use inclusive language and follow your patient’s lead. “There are many ways that people identify, both with respect to their sexual orientation and their gender identity,” he said. “We often think that a person is either gay or straight, or cisgender or transgender. There are many folks who reject these binaries and may view their gender identity or sexual orientation outside of these descriptors. You can be bisexual. You can be asexual.” He also emphasized that sexual orientation is different from sexual behavior.

Be deliberate about your phrasing. Boos said he strives to make new patients feel comfortable by asking them such questions as what pronouns they use, how he should address them, and whether they have a partner or are in a relationship. “Then, in general, just follow your patient’s lead,” Boos said. “If they’re referring to their partner in a certain way or to themselves with certain pronouns, go along with it. When in doubt, just ask. And if you make a mistake like using the wrong pronouns or name of a patient, the best thing to do is immediately apologize and try your best not to repeat that error.”

When asking about sexual practices, don’t make assumptions. Boos recommends a 2019 article on dermatologic care of LGBT persons, published in the Journal of the American Academy of Dermatology, which includes specific examples of how to elicit a sexual history from adults and teens. One of the recommendations is “to be very direct, say, ‘This may feel uncomfortable, but I have to ask you these direct questions about what you’re doing sexually because I need to understand if you’re at risk for things like sexually transmitted infections,’ ” Boos said. “It’s also important to use terminology that our patients know. If I ask someone if they’ve had sex before, they usually understand that as penile-vaginal intercourse, but it’s also important to understand if they have oral or anal sex. But if you ask, ‘Have you had insertive anal sex?’ they may not know what that means as opposed to receptive anal sex. Instead, you might ask, ‘Are you a top or a bottom?’ which are more commonly used and understood terms in the queer community. It may feel really uncomfortable to use that kind of language, but we want to make sure patients understand what we’re asking them so we can take the best possible care of them.”

Pay attention to the details. One way to demonstrate inclusivity in your practice includes collecting pronoun and sexual orientation information for the electronic medical record so your entire staff can use proper pronouns for the patient. “Also, acknowledge that for queer folks, family can mean more than just biological family,” Boos added. “I do not buy into the stereotype that all queer kids are ostracized from their families and not loved by their families, but it is true that they are at risk for those experiences. So, sometimes a member of the patient’s ‘chosen family’ accompanies them on their visit.”

Privacy is also key. “You never know who else is in the room when you’re on a telehealth call, so you need to address that before you ask about personal things,” Boos said. “One sticking point that can also come up is that parents often fill out their child’s patient demographic form, which may not tell the real story. I typically start to have confidential time without parents and may take a sexual history as early as 12 or 13 years of age if it’s a patient that I’m seeing for an extended period or if I’m worried about a skin finding that might suggest an STI.”

He highlighted the unique opportunity dermatologists have to transform the healthcare landscape for LGBTQ children and adolescents. “It’s about extending yourself to nurture the growth of another person,” Boos said. “This can feel challenging, but you want to see each person for who they are and help get them to where they want to go. That’s what we went into medicine for, right? We want to care about people.”

Boos had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.

For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
 

Case In Point: A 13-Year-Old With MG

Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”

Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.

“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”

The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.

“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
 

Consider Prescription Eye Drops for Ptosis

Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”

However, it can be difficult to get insurers to cover these medications, he said.

The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
 

The Young Patient Worsens. Now What?

The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.

Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.

However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.

Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”

Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
 

Don’t Neglect Supportive Care

Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.

He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”

How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”

Ginsberg had no disclosures.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.

For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
 

Case In Point: A 13-Year-Old With MG

Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”

Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.

“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”

The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.

“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
 

Consider Prescription Eye Drops for Ptosis

Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”

However, it can be difficult to get insurers to cover these medications, he said.

The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
 

The Young Patient Worsens. Now What?

The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.

Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.

However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.

Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”

Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
 

Don’t Neglect Supportive Care

Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.

He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”

How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”

Ginsberg had no disclosures.
 

A version of this article appeared on Medscape.com.

SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.

For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.

And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
 

Case In Point: A 13-Year-Old With MG

Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”

Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.

“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”

The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.

“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
 

Consider Prescription Eye Drops for Ptosis

Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”

However, it can be difficult to get insurers to cover these medications, he said.

The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
 

The Young Patient Worsens. Now What?

The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.

Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.

However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.

Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”

Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
 

Don’t Neglect Supportive Care

Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.

He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”

How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”

Ginsberg had no disclosures.
 

A version of this article appeared on Medscape.com.