THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

THE CASE

Michael T,* a 20-year-old cisgender male, visited one of our clinic’s primary care physicians (PCPs). He was reserved and quiet and spoke of his concerns about depression and social anxiety that had been present for several years. He also spoke of his inability to succeed at work and school. Following a thorough PCP review leading to diagnoses of major depressive disorder and social anxiety, the patient agreed to try medication. Over a period of 15 months, trials of medications including fluoxetine, sertraline, aripiprazole, and duloxetine did little to improve the patient’s mood. The PCP decided to consult with our clinic’s integrated health team.

The team reviewed several diagnostic possibilities (TABLE 1) and agreed with the PCP’s diagnoses of major depression and social anxiety. But these disorders alone did not explain the full picture. Team members noted the patient’s unusual communication style, characterized by remarkably long response times and slow processing speed. In particular, when discussing mood, he took several seconds to respond but would respond thoughtfully and with few words.

We administered the Wechsler Adult Intelligence Scale (WAIS-IV). Due to differences between the 4 indices within the WAIS-IV, the Full Scale Intelligence Quotient may under- or overestimate abilities across domains; this was the case for this patient. His General Ability Index (GAI) score was 130, in the very superior range and at the 98th percentile, placing him in the category of gifted intelligence. The patient’s processing speed, however, was at the 18th percentile, which explained his delayed response style and presence of developmental asynchrony, a concept occasionally reported when interpreting socio-emotional and educational maladjustment in gifted individuals.

We determined that Mr. T was twice exceptional—intellectually gifted and also having one or more areas of disability.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity .

In individuals with gifted intelligence, a discrepancy between cognitive and emotional development can make them vulnerable to behavioral and emotional challenges. It is not uncommon for gifted individuals to experience co-occurring distress, anxiety, depression, social withdrawal, difficulty coping with challenging tasks and experiences, low self-esteem, and excessive perfectionism.^1-6 Giftedness accompanied by a delay in general abilities and processing speed (significant verbal-performance discrepancy) places an individual in the category of twice-exceptionality, or “2E”—having the potential for high achievement while displaying evidence of 1 or more disabilities including emotional or behavioral difficulties.⁷

2E Individuals: Prevalence, characteristics, and outcomes

Reported prevalence of twice-exceptionality varies, from approximately 180,000 to 360,000 students in the United States.⁷ In 2009, the National Commission on Twice Exceptional Students provided the following definition of twice exceptionality:^7,8

2E individuals may excel early due to strong language abilities, but then show signs of disability when curricular demands rise in junior high school or later.

“Twice-exceptional learners are students who demonstrate the potential for high achievement or creative productivity in one or more domains such as math, science, technology, the social arts, the visual, spatial, or performing arts or other areas of human productivity AND who manifest one or more disabilities as defined by federal or state eligibility criteria. These disabilities include specific learning disabilities; speech and language disorders; emotional/behavioral disorders; physical disabilities; Autism Spectrum Disorders (ASD); or other health impairments, such as Attention Deficit/Hyperactivity Disorder (ADHD).”

How twice-exceptionality might manifest. The literature describes 3 unique groupings of 2E children: those who excel early due to strong language abilities, but later show signs of disability, often when curricular demands rise in junior high, high school, or even college; students diagnosed with disability, but who show exceptional gifts in some areas that may be masked by their learning difficulties; and highly intelligent students who seem to be average, because their disabilities mask their giftedness or their talents mask their difficulties.^9,10

Unique behavioral and emotional challenges of 2E individuals may include lower motivation and academic self-efficacy, low self-worth and feelings of failure, or disruptive behaviors.^7,11,12 Anxiety and depression often result from the functional impact of twice-exceptionality as well as resultant withdrawal, social isolation, and delay or hindrance of social skills (such as difficulty interpreting social cues).^13,14 The individual in our case displayed many of these challenges, including lower motivation, self-worth, and self-esteem, and comorbid anxiety and depression (TABLE 1), further clouding diagnostic clarity.

Continue to: The need for improved recognition

The need for improved recognition. Twice-exceptionality commonly manifests as children reach grade-school age, but they are underrepresented in programs for the gifted due to misunderstanding and misdiagnosis by professionals.^15,16 Best practices in identifying 2E children incorporate multidimensional assessments including pre-referral and screening, preliminary intervention, evaluation procedures, and educational planning.¹⁶ Despite research asserting that 2E individuals need more support services, knowing how to best identify and support individuals across various settings can prove difficult.^7,17-19

Primary care, as we will discuss in a bit, is an interdisciplinary setting in which identification and comprehensive and collaborative support can occur. Historically, though, mental and physical health care have been “siloed” and mental health professionals’ functions in medical settings have often been circumscribed.^20,21

A lesson from how our case unfolded

Our integrated health team, known as Integrated Behavioral Health Plus (IBH+), was developed at the University of Colorado School of Medicine, and is a system-level integration of behavioral health professionals working with medical providers to improve outcomes and satisfaction.²² Psychology supervisors and trainees, telepsychiatrists and psychiatry residents, social workers, and pharmacists work together with PCPs and residents to deliver comprehensive patient care. Our model includes a range of behavioral health access points for patients (TABLE 2) and the use of complex patient databases and care team meetings.

In the case we have described here, the nature of the patient’s presentation did not trigger any of the clinical procedures described in TABLE 2, and he fell under the radar of complex patient cases in the clinic. Instead, informal, asynchronous clinical conversations between providers were what eventually lead to diagnostic clarification. Team consultation and psychometric testing provided by IBH+ helped uncover the “hidden diagnosis” of this patient in primary care and identified him as twice-exceptional, experiencing both giftedness and significant emotional suffering (major depression and social anxiety, low self-esteem and self-worth).

Takeaways for primary care

Not all PCPs, of course, have immediate onsite access to a program such as ours. However, innovative ways to tap into available resources might include establishing a partnership with 1 or more behavioral health professionals or bridging less formal relationships with such providers in the community and schools to more easily share patient records.

Continue to: Other presentations within 2E populations

Other presentations within 2E populations. 2E individuals may have other presentations coupled with high cognitive ability⁷: symptoms of hyperactivity disorders; specific learning disabilities; a diagnosis of autism spectrum disorder (previously termed Asperger type); attention, organizational, social, and behavioral issues; and impulsivity or emotional volatility.

We shifted from a “bugs and drugs” perspective of diagnosis and treatment to an approach that explored the interplay between cognitive and emotional functioning for this individual.

Of note, the perspective of our care team shifted from a “bugs and drugs” perspective of diagnosis and treatment—biological explanations and pharmaceutical solutions—to an approach that explored the underlying interplay between cognitive and emotional functioning for this individual. Our treatment focused on a strengths-based and patient-centered approach. Even without the resources of a full IBH+ model, primary care practices may be able to adapt our experience to their ever-growing complex populations.

THE CASE

Our team shifted treatment planning to the needs of the patient. The 2E identification changed the patient’s perspective about himself. After learning of his giftedness, the patient was able to reframe himself as a highly intelligent, capable individual in need of treatment for depression and social anxiety, as opposed to questioning his intelligence and experiencing confusion and hopelessness within the medical system. His PCP collaborated with the team via telecommunication to maintain an efficacious antidepressant plan and to use a strengths-based approach focused on increasing the patient’s self-view and changing the illness narrative. This narrative was changed by practicing skills, such as challenging unhelpful thought patterns, setting beneficial boundaries, and supporting assertive communication to oppose thoughts and relationships that perpetuated old, negative beliefs and assumptions.

CORRESPONDENCE
Kathryn S. Saldaña, PhD, University of Colorado, 12631 East 17th Avenue, AO1 L15, 3rd Floor, Aurora, CO 80045; kathryn. [email protected].

ACKNOWLEDGEMENTS
Our thanks to A.F. Williams Family Medicine Clinic and the University of Colorado Anschutz Medical Campus School of Medicine for their unparalleled models of resident training and multidisciplinary care.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.

A 17-year-old high school baseball player presented to a sports medicine clinic for left anterior knee pain. During the exam, a hyperpigmented lesion was incidentally noted on his left palm. The patient, who also played basketball and football, was unsure of how long he’d had the lesion, and he did not recall having any prior lesions on his hand. He denied any discomfort or significant past medical history. There was no known family history of skin cancers, but the patient did report that his brother, also an athlete, had a similar lesion on his hand.

On closer examination, scattered black dots were noted within a 2 × 1–cm thickened keratotic plaque at the hypothenar eminence of the patient’s left hand (Figure). There was no tenderness, erythema, warmth, or disruption of normal skin architecture or drainage.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Posttraumatic tache noir (also known as talon noir on the volar aspect of the feet) is a subcorneal hematoma. The diagnosis is made clinically.

Identifying “pebbles on a ridge” or “satellite globules” during dermoscopic evaluation can differentiate benign from malignant sources of this type of lesion.

Our patient was a competitive baseball player, and he noted that the knob of his baseball bat rubbed the hypothenar eminence of his nondominant hand when he took a swing. The sheer force of the knob led to the subcorneal hematoma. Tache noir was high on the differential due to the author’s clinical experience with similar cases.

Tache noir occurs predominantly in people ages 12 to 24 years, without regard to gender.¹ The condition is commonly found in athletes who participate in baseball, cricket, racquet sports, weightlifting, and rock climbing.^1-3 Talon noir occurs most commonly in athletes who are frequently jumping, turning, and pivoting, as in football, basketball, tennis, and lacrosse. One should have a high index of suspicion for this diagnosis in patients who participate in any sport that might lead to shearing forces involving the volar aspect of the hands or feet.

Confirmation is obtained through a simple procedure. Dermoscopic evaluation of tache/talon noir will reveal “pebbles on a ridge” or “satellite globules.” Confirmation of tache/talon noir can be made by paring the corneum with a #15 blade, which will reveal blood in the shavings and punctate lesions.⁴

Other lesions may havea similar appearance

Tache noir can be differentiated from other conditions by the presence of preserved architecture of the skin surface and punctate capillaries beneath the stratum corneum. The differential diagnosis includes verruca vulgaris, acral melanoma, and a traumatic tattoo.

Continue to: Verruca vulgaris

Verruca vulgaris similarly contains puncta but typically appears as a raised lesion with a disruption of the stratum corneum.⁵

Acral melanoma can be distinguished from tache/talon noir by dermoscopic evaluation and/or paring of the corneum. On dermoscopic evaluation, both acral melanoma and tache/talon noir will reveal parallel ridge patterns; this finding has an 86% sensitivity and 96% specificity for early acral melanoma.⁶ What differentiates the 2 is the “satellite globules” or “pebbles on a ridge” that are seen with a subcorneal hematoma. Furthermore, paring the corneum would demonstrate an absence of blood within the ridges of the skin shavings, pointing away from tache/talon noir as the diagnosis.^1-3,5-7

Traumatic tattoo can also mimic tache/talon noir, due to foreign-material deposits in the skin (gunpowder, carbon, lead, dirt, and asphalt). A history of penetrating trauma should help to narrow the differential. Attempts at paring with traumatic tattoo may or may not help with differentiation.¹

In this case, time does heal all wounds

Talon/tache noir are benign conditions that do not require treatment and do not affect sports performance. The lesion will usually self-resolve within a matter of weeks from onset or can even be gently scraped with a sterile needle or blade, which can partially or completely remove the pigmentation from within the parallel ridges.^3,5,8

Our patient was advised that the lesion would resolve on its own. His knee pain was determined to be a simple case of patellofemoral syndrome or “runner’s knee” and he opted to complete a home exercise program to obtain relief.

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

When state senators in South Carolina held two hearings in September about COVID-19 treatments, they got an earful on the benefits of ivermectin — which many of the lawmakers echoed, sharing experiences of their own loved ones.

The demands for access to the drug were loud and insistent, despite federal regulators’ recent warning against using the drug to treat COVID.

Ivermectin is a generic drug  that has been used for decades to treat river blindness, scabies, and even head lice. Veterinarians also use it, in different formulations and dosages, to treat animals for parasites like worms.

At one of the South Carolina hearings, Pressley Stutts III reminded the panel that his father, a prominent GOP leader in the state, had died of COVID a month earlier. He believed ivermectin could have helped him. But doctors at the hospital wouldn’t discuss it.

“I went every bit as far as I could without getting myself thrown in jail trying to save my father’s life,” he told the panel, as lawmakers offered condolences.

“What is going on here?” he asked, with the passion in his voice growing. “My dad’s dead!”

The pleas to public officials have been building. And now politicians are beginning to act, largely to satisfy their conservative constituents.

After the pandemic began, scientists launched clinical trials to see if ivermectin could help as a treatment for COVID. Some are still ongoing. But providers in mainstream medicine have rejected it as a COVID treatment, citing the poor quality of the studies to date, and two notorious “preprint” studies that were circulated before they were peer-reviewed, and later taken off the internet because of inaccurate and flawed data.

On Aug. 26, the Centers for Disease Control and Prevention advised clinicians not to use ivermectin, citing insufficient evidence of benefit and pointing out that unauthorized use had led to accidental poisonings. Vaccination, the CDC reiterated, is still the best way to avoid serious illness and death from the coronavirus.

But many Americans remain convinced ivermectin could be beneficial, and some politicians appear to be listening to them.

“If we have medications out here that are working — or seem to be working — I think it’s absolutely horrible that we’re not trying them,” said Republican state Sen. Tom Corbin in South Carolina. He questioned doctors who had come to the Statehouse to counter efforts to move ivermectin into mainstream use.

The doctors challenged the implied insult that they weren’t following best practices: “Any implication that any of us would do anything to withhold effective treatments from our patients is really insulting to our profession,” said Dr. Annie Andrews, a professor at the Medical University of South Carolina who has cared for COVID patients throughout the pandemic.

Instead of listening to the medical consensus, some politicians in states like South Carolina seem to be taking cues from doctors on the fringe. During one September hearing, state senators patched in a call from Dr. Pierre Kory.

They know better now, she said.

“My first attempt would have been to keep her out of the hospital,” Ms. Berry said. “Because right now when you go to the hospital, they only give you what’s on the CDC protocol.”

Ms. Berry and her husband have purchased their own supply of ivermectin, which they keep at home.

This story is from a partnership that includes NPR, Nashville Public Radio and  KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

When state senators in South Carolina held two hearings in September about COVID-19 treatments, they got an earful on the benefits of ivermectin — which many of the lawmakers echoed, sharing experiences of their own loved ones.

The demands for access to the drug were loud and insistent, despite federal regulators’ recent warning against using the drug to treat COVID.

Ivermectin is a generic drug  that has been used for decades to treat river blindness, scabies, and even head lice. Veterinarians also use it, in different formulations and dosages, to treat animals for parasites like worms.

At one of the South Carolina hearings, Pressley Stutts III reminded the panel that his father, a prominent GOP leader in the state, had died of COVID a month earlier. He believed ivermectin could have helped him. But doctors at the hospital wouldn’t discuss it.

“I went every bit as far as I could without getting myself thrown in jail trying to save my father’s life,” he told the panel, as lawmakers offered condolences.

“What is going on here?” he asked, with the passion in his voice growing. “My dad’s dead!”

The pleas to public officials have been building. And now politicians are beginning to act, largely to satisfy their conservative constituents.

After the pandemic began, scientists launched clinical trials to see if ivermectin could help as a treatment for COVID. Some are still ongoing. But providers in mainstream medicine have rejected it as a COVID treatment, citing the poor quality of the studies to date, and two notorious “preprint” studies that were circulated before they were peer-reviewed, and later taken off the internet because of inaccurate and flawed data.

On Aug. 26, the Centers for Disease Control and Prevention advised clinicians not to use ivermectin, citing insufficient evidence of benefit and pointing out that unauthorized use had led to accidental poisonings. Vaccination, the CDC reiterated, is still the best way to avoid serious illness and death from the coronavirus.

But many Americans remain convinced ivermectin could be beneficial, and some politicians appear to be listening to them.

“If we have medications out here that are working — or seem to be working — I think it’s absolutely horrible that we’re not trying them,” said Republican state Sen. Tom Corbin in South Carolina. He questioned doctors who had come to the Statehouse to counter efforts to move ivermectin into mainstream use.

The doctors challenged the implied insult that they weren’t following best practices: “Any implication that any of us would do anything to withhold effective treatments from our patients is really insulting to our profession,” said Dr. Annie Andrews, a professor at the Medical University of South Carolina who has cared for COVID patients throughout the pandemic.

Instead of listening to the medical consensus, some politicians in states like South Carolina seem to be taking cues from doctors on the fringe. During one September hearing, state senators patched in a call from Dr. Pierre Kory.

They know better now, she said.

“My first attempt would have been to keep her out of the hospital,” Ms. Berry said. “Because right now when you go to the hospital, they only give you what’s on the CDC protocol.”

Ms. Berry and her husband have purchased their own supply of ivermectin, which they keep at home.

This story is from a partnership that includes NPR, Nashville Public Radio and  KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

When state senators in South Carolina held two hearings in September about COVID-19 treatments, they got an earful on the benefits of ivermectin — which many of the lawmakers echoed, sharing experiences of their own loved ones.

The demands for access to the drug were loud and insistent, despite federal regulators’ recent warning against using the drug to treat COVID.

Ivermectin is a generic drug  that has been used for decades to treat river blindness, scabies, and even head lice. Veterinarians also use it, in different formulations and dosages, to treat animals for parasites like worms.

At one of the South Carolina hearings, Pressley Stutts III reminded the panel that his father, a prominent GOP leader in the state, had died of COVID a month earlier. He believed ivermectin could have helped him. But doctors at the hospital wouldn’t discuss it.

“I went every bit as far as I could without getting myself thrown in jail trying to save my father’s life,” he told the panel, as lawmakers offered condolences.

“What is going on here?” he asked, with the passion in his voice growing. “My dad’s dead!”

The pleas to public officials have been building. And now politicians are beginning to act, largely to satisfy their conservative constituents.

After the pandemic began, scientists launched clinical trials to see if ivermectin could help as a treatment for COVID. Some are still ongoing. But providers in mainstream medicine have rejected it as a COVID treatment, citing the poor quality of the studies to date, and two notorious “preprint” studies that were circulated before they were peer-reviewed, and later taken off the internet because of inaccurate and flawed data.

On Aug. 26, the Centers for Disease Control and Prevention advised clinicians not to use ivermectin, citing insufficient evidence of benefit and pointing out that unauthorized use had led to accidental poisonings. Vaccination, the CDC reiterated, is still the best way to avoid serious illness and death from the coronavirus.

But many Americans remain convinced ivermectin could be beneficial, and some politicians appear to be listening to them.

“If we have medications out here that are working — or seem to be working — I think it’s absolutely horrible that we’re not trying them,” said Republican state Sen. Tom Corbin in South Carolina. He questioned doctors who had come to the Statehouse to counter efforts to move ivermectin into mainstream use.

The doctors challenged the implied insult that they weren’t following best practices: “Any implication that any of us would do anything to withhold effective treatments from our patients is really insulting to our profession,” said Dr. Annie Andrews, a professor at the Medical University of South Carolina who has cared for COVID patients throughout the pandemic.

Instead of listening to the medical consensus, some politicians in states like South Carolina seem to be taking cues from doctors on the fringe. During one September hearing, state senators patched in a call from Dr. Pierre Kory.

They know better now, she said.

“My first attempt would have been to keep her out of the hospital,” Ms. Berry said. “Because right now when you go to the hospital, they only give you what’s on the CDC protocol.”

Ms. Berry and her husband have purchased their own supply of ivermectin, which they keep at home.

This story is from a partnership that includes NPR, Nashville Public Radio and  KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

It’s rare for mothers with COVID-19 to transfer the infection to their newborns, according to a new small study.

The research, published in JAMA Network Open, found that newborns of mothers infected with the COVID-19 virus were able to develop their own immune defenses via their mother’s breast milk. Researchers detected antibodies in the infants’ saliva.

“It is the first time that this mechanism has been demonstrated,” said study author Rita Carsetti, MD, head of immunology diagnostics for Bambino Gesù Children’s Hospital in Rome. “We now know how breast milk can help babies develop their immune defenses. The system could work the same way for many other pathogens, which are present in the mother during breastfeeding.”

Dr. Carsetti and colleagues examined data from 28 pregnant women who tested positive for COVID-19 and who gave birth at Policlinico Umberto I in Rome between November 2020 and May 2021, and their newborns. They investigated the immune responses of the mothers and their newborns by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breast milk and infant saliva 48 hours after delivery and 2 months later.

Twenty-one mothers and their newborns completed the 2 months of follow-up. Researchers found that the majority of the mothers had mild symptoms of COVID-19, while only three of them were admitted for worsening condition. There was only one reported case of a possible vertical transmission – transmitted in utero – and one case of a horizontal infection through droplets or respiratory secretions, which occurred when the newborn was taken home.

The results of the study showed that antibodies specific to the virus were present in the mothers’ blood at 2 months after delivery, but not at 48 hours. However, in milk, specific antibodies were already present 48 hours after delivery.

Therefore, after 48 hours, the breastfed babies had specific mucosal antibodies against COVID-19 in their saliva that the other newborns did not have. Two months later, these antibodies continued to be present even though the mothers had stopped producing them.

The findings suggest that breast milk offers protection by transferring the antibodies produced by the mother to the baby, but also by helping them to produce their own immune defenses.

“I am not surprised that infants of mothers who had COVID-19 infection in the peripartum period pass anti-spike protein IgA to their infants,” J. Howard Smart, MD, FAAP, who was not involved with the study, said in an interview. “This confirmation is good news for breastfeeding mothers.

“I wonder whether we really know these infants did not become infected, and produce their own antibodies,” said Dr. Smart, chairman of the department of pediatrics at Sharp Rees-Stealy Medical Group in San Diego.

The American College of Obstetricians and Gynecologists said having COVID-19 should not stop mothers from giving their children breast milk. The organization also said that the chance of COVID-19 passing through the breast milk and causing infection in the newborn infant is slim.

“Breast milk also helps protect babies from infections, including infections of the ears, lungs, and digestive system. For these reasons, having COVID-19 should not stop you from giving your baby breast milk,” according to ACOG’s website.

Similar studies on mothers who received the COVID-19 vaccination rather than being infected would be interesting, Dr. Smart added.

The authors of the current study plan to broaden their research by evaluating the response of pregnant mothers vaccinated against SARS-CoV-2 for the presence of antibodies in the milk and the immunity of their newborns. Dr. Carsetti said her team plans to expand the study to other infections, such as cytomegalovirus and respiratory syncytial virus.

None of the researchers or commentators had financial disclosures.

It’s rare for mothers with COVID-19 to transfer the infection to their newborns, according to a new small study.

The research, published in JAMA Network Open, found that newborns of mothers infected with the COVID-19 virus were able to develop their own immune defenses via their mother’s breast milk. Researchers detected antibodies in the infants’ saliva.

“It is the first time that this mechanism has been demonstrated,” said study author Rita Carsetti, MD, head of immunology diagnostics for Bambino Gesù Children’s Hospital in Rome. “We now know how breast milk can help babies develop their immune defenses. The system could work the same way for many other pathogens, which are present in the mother during breastfeeding.”

Dr. Carsetti and colleagues examined data from 28 pregnant women who tested positive for COVID-19 and who gave birth at Policlinico Umberto I in Rome between November 2020 and May 2021, and their newborns. They investigated the immune responses of the mothers and their newborns by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breast milk and infant saliva 48 hours after delivery and 2 months later.

Twenty-one mothers and their newborns completed the 2 months of follow-up. Researchers found that the majority of the mothers had mild symptoms of COVID-19, while only three of them were admitted for worsening condition. There was only one reported case of a possible vertical transmission – transmitted in utero – and one case of a horizontal infection through droplets or respiratory secretions, which occurred when the newborn was taken home.

The results of the study showed that antibodies specific to the virus were present in the mothers’ blood at 2 months after delivery, but not at 48 hours. However, in milk, specific antibodies were already present 48 hours after delivery.

Therefore, after 48 hours, the breastfed babies had specific mucosal antibodies against COVID-19 in their saliva that the other newborns did not have. Two months later, these antibodies continued to be present even though the mothers had stopped producing them.

The findings suggest that breast milk offers protection by transferring the antibodies produced by the mother to the baby, but also by helping them to produce their own immune defenses.

“I am not surprised that infants of mothers who had COVID-19 infection in the peripartum period pass anti-spike protein IgA to their infants,” J. Howard Smart, MD, FAAP, who was not involved with the study, said in an interview. “This confirmation is good news for breastfeeding mothers.

“I wonder whether we really know these infants did not become infected, and produce their own antibodies,” said Dr. Smart, chairman of the department of pediatrics at Sharp Rees-Stealy Medical Group in San Diego.

The American College of Obstetricians and Gynecologists said having COVID-19 should not stop mothers from giving their children breast milk. The organization also said that the chance of COVID-19 passing through the breast milk and causing infection in the newborn infant is slim.

“Breast milk also helps protect babies from infections, including infections of the ears, lungs, and digestive system. For these reasons, having COVID-19 should not stop you from giving your baby breast milk,” according to ACOG’s website.

Similar studies on mothers who received the COVID-19 vaccination rather than being infected would be interesting, Dr. Smart added.

The authors of the current study plan to broaden their research by evaluating the response of pregnant mothers vaccinated against SARS-CoV-2 for the presence of antibodies in the milk and the immunity of their newborns. Dr. Carsetti said her team plans to expand the study to other infections, such as cytomegalovirus and respiratory syncytial virus.

None of the researchers or commentators had financial disclosures.

It’s rare for mothers with COVID-19 to transfer the infection to their newborns, according to a new small study.

The research, published in JAMA Network Open, found that newborns of mothers infected with the COVID-19 virus were able to develop their own immune defenses via their mother’s breast milk. Researchers detected antibodies in the infants’ saliva.

“It is the first time that this mechanism has been demonstrated,” said study author Rita Carsetti, MD, head of immunology diagnostics for Bambino Gesù Children’s Hospital in Rome. “We now know how breast milk can help babies develop their immune defenses. The system could work the same way for many other pathogens, which are present in the mother during breastfeeding.”

Dr. Carsetti and colleagues examined data from 28 pregnant women who tested positive for COVID-19 and who gave birth at Policlinico Umberto I in Rome between November 2020 and May 2021, and their newborns. They investigated the immune responses of the mothers and their newborns by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breast milk and infant saliva 48 hours after delivery and 2 months later.

Twenty-one mothers and their newborns completed the 2 months of follow-up. Researchers found that the majority of the mothers had mild symptoms of COVID-19, while only three of them were admitted for worsening condition. There was only one reported case of a possible vertical transmission – transmitted in utero – and one case of a horizontal infection through droplets or respiratory secretions, which occurred when the newborn was taken home.

The results of the study showed that antibodies specific to the virus were present in the mothers’ blood at 2 months after delivery, but not at 48 hours. However, in milk, specific antibodies were already present 48 hours after delivery.

Therefore, after 48 hours, the breastfed babies had specific mucosal antibodies against COVID-19 in their saliva that the other newborns did not have. Two months later, these antibodies continued to be present even though the mothers had stopped producing them.

The findings suggest that breast milk offers protection by transferring the antibodies produced by the mother to the baby, but also by helping them to produce their own immune defenses.

“I am not surprised that infants of mothers who had COVID-19 infection in the peripartum period pass anti-spike protein IgA to their infants,” J. Howard Smart, MD, FAAP, who was not involved with the study, said in an interview. “This confirmation is good news for breastfeeding mothers.

“I wonder whether we really know these infants did not become infected, and produce their own antibodies,” said Dr. Smart, chairman of the department of pediatrics at Sharp Rees-Stealy Medical Group in San Diego.

The American College of Obstetricians and Gynecologists said having COVID-19 should not stop mothers from giving their children breast milk. The organization also said that the chance of COVID-19 passing through the breast milk and causing infection in the newborn infant is slim.

“Breast milk also helps protect babies from infections, including infections of the ears, lungs, and digestive system. For these reasons, having COVID-19 should not stop you from giving your baby breast milk,” according to ACOG’s website.

Similar studies on mothers who received the COVID-19 vaccination rather than being infected would be interesting, Dr. Smart added.

The authors of the current study plan to broaden their research by evaluating the response of pregnant mothers vaccinated against SARS-CoV-2 for the presence of antibodies in the milk and the immunity of their newborns. Dr. Carsetti said her team plans to expand the study to other infections, such as cytomegalovirus and respiratory syncytial virus.

None of the researchers or commentators had financial disclosures.

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

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

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

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

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

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

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.

Adults and children with acute or chronic leukemias

A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.

Mast-cell leukemia (MCL)

Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.

Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)

Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.

High-grade myeloid cancers with measurable residual disease

Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.

Newly diagnosed Philadelphia-negative ALL

Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.

Untreated adults with TP53-mutant AML

Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).

All trial information is from the U.S. National Library of Medicine, National Institutes of Health.

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

A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.

Adults and children with acute or chronic leukemias

A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.

Mast-cell leukemia (MCL)

Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.

Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)

Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.

High-grade myeloid cancers with measurable residual disease

Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.

Newly diagnosed Philadelphia-negative ALL

Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.

Untreated adults with TP53-mutant AML

Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).

All trial information is from the U.S. National Library of Medicine, National Institutes of Health.

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

A number of late-phase clinical trials in leukemia have opened in recent months. Maybe one of your patients could benefit from being enrolled.

Adults and children with acute or chronic leukemias

A phase 2 study partnering with the National Marrow Donor Program is seeking individuals aged 1-65 years with lymphoma or one of the following leukemias: “acute leukemia”, acute lymphoblastic (ALL), acute myelogenous (AML), mixed-phenotype acute, chronic myelogenous (CML), and chronic lymphocytic (CLL). Researchers hope to find a way to improve outcomes of hematopoietic-cell transplantation from mismatched, unrelated donors. Participants will receive the transplant and one of seven drug regimens and will be followed for a year. The trial plans to enroll 180 people and began recruiting on Sept. 30 in California, New York, and Virginia. The primary outcome is overall survival (OS). Quality of life (QoL) will not be measured.

Mast-cell leukemia (MCL)

Adults with MCL are sought for a phase 2 study of bezuclastinib, an experimental tyrosine-kinase inhibitor (TKI) called CGT9486. CGT9486 blocks the activity of a mutated version of tyrosine-kinase receptor KIT, called KIT D816V, which is known to cause systemic mastocytosis. Participants will receive oral CGT9486 daily for up to 18 months. The study opened in October, aiming for 140 participants with any advanced systemic mastocytoses (including MCL) at sites in California, Florida, Massachusetts, New York, Ohio, Texas, and Utah. OS and QoL will be tracked.

Previously Treated CLL/Small Lymphocytic Lymphoma (SLL)

Patients with CLL/SLL who have progressed on previous therapy can join a phase 3 study of another experimental oral TIK, pirtobrutinib, this time targeting Bruton’s tyrosine kinase (BTK). BTK plays a key role in the lifecycle of white blood cells. Participants will receive either “fixed-duration” pirtobrutinib plus venetoclax (Venclexta) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera) or the venetoclax-rituximab combo only, for up to 5 years. Investigators started recruiting in September, aiming for 600 participants across Florida, Louisiana, Missouri, New York, and Tennessee. Progression-free survival is the primary outcome; OS is a secondary outcome and QoL will not be tracked.

High-grade myeloid cancers with measurable residual disease

Patients with AML, myelodysplastic syndrome with excess blasts-2 or myeloid neoplasm, and whose original disease is still present, are eligible for a phase 2 study of CPX-351 (daunorubicin-cytarabine, Vyxeos). The intravenous chemotherapy was approved in 2017 for certain types of AML. The goal of this study is to determine if pretreatment with CPX-351 improves the outcome of donor stem-cell transplantation. Patients will either undergo immediate transplantation or receive CPX-351 for up to 10 days followed 60 days later by the transplant. The study, being conducted at the Fred Hutchinson Cancer Research Center in Seattle, started recruiting 130 patients in August. The primary outcome is OS; QoL will not be tracked.

Newly diagnosed Philadelphia-negative ALL

Patients aged 22 or older with Philadelphia-negative ALL who have not received chemotherapy or radiation therapy are invited to join a trial of calaspargase pegol (Asparlas). The therapy was approved in 2018 for ALL in children and young adults (1 month to 21 years). The aim of this study is to confirm the recommended doses and evaluate the drug’s safety and pharmacodynamics in adults over aged 21. Each participant will receive six 2-hour infusions of calaspargase pegol over several months. The primary outcomes are safety and drug activity; OS is a secondary outcome and QoL will not be measured. The study opened on July 7 and aims to recruit 122 participants in 11 states.

Untreated adults with TP53-mutant AML

Adult patients with previously untreated AML who have at least one TP53 gene mutation are sought for a phase 3 study of magrolimab, an investigational anti-CD47 monoclonal antibody. Participants will be treated for up to 27 months with either magrolimab plus azacytidine (Vidaza), venetoclax plus azacytidine (patients deemed “appropriate for nonintensive therapy”), or standard chemotherapy (those “appropriate for intensive therapy”). In patients who received nonintensive therapy, OS is the primary outcome; OS in all participants is a secondary outcome, and QoL won’t be assessed. The trial opened in July and aims to recruit 346 individuals in Hong Kong, Australia, and the United States (California, Missouri, Oklahoma, Pennsylvania, South Carolina, and Texas).

All trial information is from the U.S. National Library of Medicine, National Institutes of Health.

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

Exposure to arsenic and other metals in utero is associated with an elevated risk for atopic dermatitis in children, researchers report in a study published Oct. 27, 2021, in JAMA Network Open.

In this multicenter cohort study, led by epidemiologist Shu-Li Wang, PhD, of the National Institute of Environmental Health Sciences, in Taiwan, each twofold increase in prenatal arsenic level correlated with a 2.4-fold higher rate of atopic dermatitis in 4-year-olds.

Atopic diseases have been on the rise. Eczema (atopic dermatitis) is the first stage of the so-called atopic march, followed by food allergies, allergic rhinitis, and asthma later in childhood. Previous research has linked heavy metal exposure to allergic diseases in adults. In another study by Dr. Wang and colleagues that was published in 2021, prenatal and early-life arsenic exposure was found to correlate with higher rates of allergic rhinitis and asthma in children. In that study, the participants were followed every 2-3 years through the age of 14 as part of the Taiwan Maternal and Infant Cohort Study.

The new study included 370 mother and child pairs who were enrolled in that birth cohort study between October 2012 and May 2015. During their third trimester of pregnancy, women completed questionnaires about their lifestyle, diet, and living environment. In addition, their height, weight, and blood pressure were recorded, and urine samples were taken. In follow-up interviews 3-4 years later, the mothers were asked whether their child had ever been diagnosed with atopic dermatitis.

The researchers used an inductively coupled plasma mass spectrometer to analyze the participants’ urine samples. They assessed for exposures in utero to eight metals: arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc.

Each unit increase of an index that estimates the combined exposure to these metals during pregnancy was associated with 63% higher odds of atopic dermatitis in the children by age 4. The researchers adjusted for parental allergies (yes or no), mother’s educational level (<12 years, 13-16 years, or >16 years), geographic area (central or eastern Taiwan), exposure to tobacco smoke during pregnancy, and the child’s gender. Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal coexposure index.

A wealth of previous research links arsenic exposure during adulthood to skin disease and immune dysfunction. Early-life arsenic exposure has been linked with elevated risk for various adult disorders, including cancer, diabetes, and heart disease, years later. In light of such research, “the findings in this paper are not surprising,” J. Christopher States, PhD, director of the Center for Integrative Environmental Health Science at the University of Louisville (Ky.), told this news organization. “Low-level arsenic exposure does not cause disease immediately, but it does appear to have long-lasting effects, making individuals susceptible to ‘second hits’ with another environmental agent.”

Research into the molecular mechanisms for these links has shown that arsenic and cadmium exposure can promote allergic phenotypes in immune cells. “We think the toxic metals activate the alarmin pathway, thus inducing innate lymphoid cells, then activating T-helper 2 cells, which drive immunoglobulin E production and breakdown of the epithelium and promotion of allergies,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University. Dr. Nadeau led that study, published in 2017 in PLOS One, along with epidemiologist Margaret Karagas, PhD, of Geisel School of Medicine at Dartmouth, Hanover, N.H.

As for what pregnant women can do to minimize their exposure to heavy metals, “that is a difficult problem and primarily a function of where one lives,” said Dr. States.

Drinking water and food are major sources of arsenic exposure. Groundwater is naturally contaminated with arsenic deposits that seep in from bedrock, said Dr. States. The U.S. Environmental Protection Agency regulates arsenic levels in public drinking water that is supplied to more than a few thousand people. However, small water supplies and private wells are unregulated, he said, and having these water sources tested for arsenic or fitted with systems to reduce arsenic can be very expensive.

Among foods, rice can have high concentrations of arsenic, Dr. Karagas told this news organization. To minimize arsenic exposure through the diet, women can limit rice-based foods, according to a web-based tool developed by her and coworkers.

In addition, tobacco smoke is a major source of cadmium exposure and a moderate source of arsenic exposure, Dr. States noted. Women can reduce their exposure to these metals by avoiding tobacco and secondhand smoke.

The study was supported by grants from the National Health Research Institutes, Chung Shan Medical University Hospital, Taiwan Ministry of Science and Technology, and the Taiwan Environmental Protection Administration. The authors and quoted experts report no relevant financial relationships.

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

Exposure to arsenic and other metals in utero is associated with an elevated risk for atopic dermatitis in children, researchers report in a study published Oct. 27, 2021, in JAMA Network Open.

In this multicenter cohort study, led by epidemiologist Shu-Li Wang, PhD, of the National Institute of Environmental Health Sciences, in Taiwan, each twofold increase in prenatal arsenic level correlated with a 2.4-fold higher rate of atopic dermatitis in 4-year-olds.

Atopic diseases have been on the rise. Eczema (atopic dermatitis) is the first stage of the so-called atopic march, followed by food allergies, allergic rhinitis, and asthma later in childhood. Previous research has linked heavy metal exposure to allergic diseases in adults. In another study by Dr. Wang and colleagues that was published in 2021, prenatal and early-life arsenic exposure was found to correlate with higher rates of allergic rhinitis and asthma in children. In that study, the participants were followed every 2-3 years through the age of 14 as part of the Taiwan Maternal and Infant Cohort Study.

The new study included 370 mother and child pairs who were enrolled in that birth cohort study between October 2012 and May 2015. During their third trimester of pregnancy, women completed questionnaires about their lifestyle, diet, and living environment. In addition, their height, weight, and blood pressure were recorded, and urine samples were taken. In follow-up interviews 3-4 years later, the mothers were asked whether their child had ever been diagnosed with atopic dermatitis.

The researchers used an inductively coupled plasma mass spectrometer to analyze the participants’ urine samples. They assessed for exposures in utero to eight metals: arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc.

Each unit increase of an index that estimates the combined exposure to these metals during pregnancy was associated with 63% higher odds of atopic dermatitis in the children by age 4. The researchers adjusted for parental allergies (yes or no), mother’s educational level (<12 years, 13-16 years, or >16 years), geographic area (central or eastern Taiwan), exposure to tobacco smoke during pregnancy, and the child’s gender. Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal coexposure index.

A wealth of previous research links arsenic exposure during adulthood to skin disease and immune dysfunction. Early-life arsenic exposure has been linked with elevated risk for various adult disorders, including cancer, diabetes, and heart disease, years later. In light of such research, “the findings in this paper are not surprising,” J. Christopher States, PhD, director of the Center for Integrative Environmental Health Science at the University of Louisville (Ky.), told this news organization. “Low-level arsenic exposure does not cause disease immediately, but it does appear to have long-lasting effects, making individuals susceptible to ‘second hits’ with another environmental agent.”

Research into the molecular mechanisms for these links has shown that arsenic and cadmium exposure can promote allergic phenotypes in immune cells. “We think the toxic metals activate the alarmin pathway, thus inducing innate lymphoid cells, then activating T-helper 2 cells, which drive immunoglobulin E production and breakdown of the epithelium and promotion of allergies,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University. Dr. Nadeau led that study, published in 2017 in PLOS One, along with epidemiologist Margaret Karagas, PhD, of Geisel School of Medicine at Dartmouth, Hanover, N.H.

As for what pregnant women can do to minimize their exposure to heavy metals, “that is a difficult problem and primarily a function of where one lives,” said Dr. States.

Drinking water and food are major sources of arsenic exposure. Groundwater is naturally contaminated with arsenic deposits that seep in from bedrock, said Dr. States. The U.S. Environmental Protection Agency regulates arsenic levels in public drinking water that is supplied to more than a few thousand people. However, small water supplies and private wells are unregulated, he said, and having these water sources tested for arsenic or fitted with systems to reduce arsenic can be very expensive.

Among foods, rice can have high concentrations of arsenic, Dr. Karagas told this news organization. To minimize arsenic exposure through the diet, women can limit rice-based foods, according to a web-based tool developed by her and coworkers.

In addition, tobacco smoke is a major source of cadmium exposure and a moderate source of arsenic exposure, Dr. States noted. Women can reduce their exposure to these metals by avoiding tobacco and secondhand smoke.

The study was supported by grants from the National Health Research Institutes, Chung Shan Medical University Hospital, Taiwan Ministry of Science and Technology, and the Taiwan Environmental Protection Administration. The authors and quoted experts report no relevant financial relationships.

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

Exposure to arsenic and other metals in utero is associated with an elevated risk for atopic dermatitis in children, researchers report in a study published Oct. 27, 2021, in JAMA Network Open.

In this multicenter cohort study, led by epidemiologist Shu-Li Wang, PhD, of the National Institute of Environmental Health Sciences, in Taiwan, each twofold increase in prenatal arsenic level correlated with a 2.4-fold higher rate of atopic dermatitis in 4-year-olds.

Atopic diseases have been on the rise. Eczema (atopic dermatitis) is the first stage of the so-called atopic march, followed by food allergies, allergic rhinitis, and asthma later in childhood. Previous research has linked heavy metal exposure to allergic diseases in adults. In another study by Dr. Wang and colleagues that was published in 2021, prenatal and early-life arsenic exposure was found to correlate with higher rates of allergic rhinitis and asthma in children. In that study, the participants were followed every 2-3 years through the age of 14 as part of the Taiwan Maternal and Infant Cohort Study.

The new study included 370 mother and child pairs who were enrolled in that birth cohort study between October 2012 and May 2015. During their third trimester of pregnancy, women completed questionnaires about their lifestyle, diet, and living environment. In addition, their height, weight, and blood pressure were recorded, and urine samples were taken. In follow-up interviews 3-4 years later, the mothers were asked whether their child had ever been diagnosed with atopic dermatitis.

The researchers used an inductively coupled plasma mass spectrometer to analyze the participants’ urine samples. They assessed for exposures in utero to eight metals: arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc.

Each unit increase of an index that estimates the combined exposure to these metals during pregnancy was associated with 63% higher odds of atopic dermatitis in the children by age 4. The researchers adjusted for parental allergies (yes or no), mother’s educational level (<12 years, 13-16 years, or >16 years), geographic area (central or eastern Taiwan), exposure to tobacco smoke during pregnancy, and the child’s gender. Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal coexposure index.

A wealth of previous research links arsenic exposure during adulthood to skin disease and immune dysfunction. Early-life arsenic exposure has been linked with elevated risk for various adult disorders, including cancer, diabetes, and heart disease, years later. In light of such research, “the findings in this paper are not surprising,” J. Christopher States, PhD, director of the Center for Integrative Environmental Health Science at the University of Louisville (Ky.), told this news organization. “Low-level arsenic exposure does not cause disease immediately, but it does appear to have long-lasting effects, making individuals susceptible to ‘second hits’ with another environmental agent.”

Research into the molecular mechanisms for these links has shown that arsenic and cadmium exposure can promote allergic phenotypes in immune cells. “We think the toxic metals activate the alarmin pathway, thus inducing innate lymphoid cells, then activating T-helper 2 cells, which drive immunoglobulin E production and breakdown of the epithelium and promotion of allergies,” said Kari Nadeau, MD, PhD, director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University. Dr. Nadeau led that study, published in 2017 in PLOS One, along with epidemiologist Margaret Karagas, PhD, of Geisel School of Medicine at Dartmouth, Hanover, N.H.

As for what pregnant women can do to minimize their exposure to heavy metals, “that is a difficult problem and primarily a function of where one lives,” said Dr. States.

Drinking water and food are major sources of arsenic exposure. Groundwater is naturally contaminated with arsenic deposits that seep in from bedrock, said Dr. States. The U.S. Environmental Protection Agency regulates arsenic levels in public drinking water that is supplied to more than a few thousand people. However, small water supplies and private wells are unregulated, he said, and having these water sources tested for arsenic or fitted with systems to reduce arsenic can be very expensive.

Among foods, rice can have high concentrations of arsenic, Dr. Karagas told this news organization. To minimize arsenic exposure through the diet, women can limit rice-based foods, according to a web-based tool developed by her and coworkers.

In addition, tobacco smoke is a major source of cadmium exposure and a moderate source of arsenic exposure, Dr. States noted. Women can reduce their exposure to these metals by avoiding tobacco and secondhand smoke.

The study was supported by grants from the National Health Research Institutes, Chung Shan Medical University Hospital, Taiwan Ministry of Science and Technology, and the Taiwan Environmental Protection Administration. The authors and quoted experts report no relevant financial relationships.

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

“When considering the challenges of obesity, ask yourself: ‘If it were diabetes, cancer, HIV, or Alzheimer’s, how would you discuss it, approach it, assess it, treat it?’” Lee M. Kaplan, MD, PhD, asked the audience of health care professionals during ObesityWeek®, the annual meeting of The Obesity Society.

“And then do it for obesity, using the full spectrum of tools at our disposal,” he advised.

This was the takeaway that Dr. Kaplan, director of the Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital and associate professor, Harvard Medical School, Boston, left the audience with at the end of his lecture entitled, “What does the future of obesity care look like?”

Invited to summarize his main points, Dr. Kaplan told this news organization in an interview that practitioners caring for patients with obesity need to first “recognize that obesity is a disease” caused by dysfunction of the metabolic system that regulates body fat – in the same way immune dysregulation can lead to asthma.

Second, “we are finally developing noninvasive therapies that are more effective,” he noted, referring to the recently approved semaglutide, and even more potent weight-loss therapies that could be on the market within 3 years, so that weight-loss outcomes with pharmacotherapy are approaching those with bariatric surgery.

Third, it is important that patients with obesity get “broad and equitable access” to treatment, and health care practitioners need to be on the same page and have a “shared understanding” of which treatments are appropriate for individual patients, “just as we do for other diseases.”  
 

Need for a shared understanding

“Dr. Kaplan really brought home the idea that we all need a shared understanding of what obesity is – and what it is not,” agreed symposium moderator Donna H. Ryan, MD, in an email.

“He underscored the biologic basis of obesity,” noted Dr. Ryan, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana, and associate editor-in-chief of Obesity, the official journal of The Obesity Society.

“It is a dysregulation of the body’s weight (especially adipose tissue) regulatory system,” she continued. “The body responds to powerful environmental pressures that produce excess energy balance, and we store that as fat and defend our highest fat mass. This makes obesity a disease, a chronic disease that requires a medical approach to reverse. It’s not a cosmetic problem, it’s a medical problem,” she emphasized.

There is so much misinformation out there about obesity, according to Dr. Ryan.

“People think it’s a lack of willpower, and even patients blame themselves for not being able to lose weight and keep it off. It’s not their fault! It’s biology.”

Although the supplement industry and fad diets falsely promise fast results, there is no magic diet, she continued.

“But we have made progress based on understanding the biologic basis of obesity and have new medications that offer real hope for patients.” 

“With 42% of U.S. adults having a BMI that qualifies as obesity, we need a concerted and broad effort to address this problem, and that starts with everybody on the same page as to what obesity is ... a shared understanding of the biologic basis of obesity. It’s time to take obesity seriously,” she summarized, echoing Dr. Kaplan.
 

A question of biology

“Obesity results from inappropriate pathophysiological regulation of body fat mass,” when the body defends adiposity, Dr. Kaplan explained at the start of his lecture.

The treatment strategy for obesity has always been a stepwise approach starting with lifestyle changes, then pharmacotherapy, then possibly bariatric surgery – each step with a potentially greater chance of weight loss. But now, he explained, medicine is on the verge of having an armamentarium of more potent weight-loss medications.

Compared with phentermine/topiramate, orlistat, naltrexone/bupropion, and liraglutide – which roughly might provide 5% to 10% weight loss, the glucagon-like peptide-1 (GLP-1) agonist semaglutide 2.4 mg/week (Wegovy, Novo Nordisk), approved by the U.S. Food and Drug Association in June, provides almost double this potential weight loss.

And two new agents that could provide “never seen before weight loss” of 25% could potentially enter the marketplace by 2025: the amylin agonist cagrilintide (Novo Nordisk) and the twincretin tirzepatide (Eli Lilly) (a combined glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 receptor agonist).

In addition, when liraglutide comes off patent, a generic version could potentially be introduced, and combined generic liraglutide plus generic phentermine/topiramate could be a less expensive weight-loss treatment option in the future, he noted.
 

One size does not fit all

Importantly, weight loss varies widely among individual patients.

A graph of potential weight loss with different treatments (for example, bariatric surgery or liraglutide) versus the percentage of patients that attain the weight losses is roughly bell-shaped, Dr. Kaplan explained. For example, in the STEP1 trial of semaglutide, roughly 7.1% of patients lost less than 5% of their initial weight, 25% of patients lost 20% to 30%, and 10.8% of patients lost 30% or more; that is, patients at the higher end had weight loss comparable to that seen with bariatric surgery

Adding pharmacotherapy after bariatric surgery could be synergistic. For example, in the GRAVITAS study of patients with type 2 diabetes who had gastric bypass surgery, those who received liraglutide after surgery had augmented weight loss compared with those who received placebo.

People at a cocktail party might come up to him and say, “I’d like to lose 5 pounds, 10 pounds,” Dr. Kaplan related in the Q&A session.

“That’s not obesity,” he emphasized. Obesity is excess body fat that poses a risk to health. A person with obesity may have 50 or more excess pounds, and the body is trying to defend this weight.

“If we want to treat obesity more effectively, we have to fully understand why it is a disease and how that disease differs from the cultural desire for thinness,” he reiterated.

“We have to keep the needs and goals of all people living with obesity foremost in our minds, even if many of them have been previously misled by the bias, stigma, blame, and discrimination that surrounds them.”

“We need to re-evaluate what we think we know about obesity and open our minds to new ideas,” he added.

Dr. Kaplan has reported financial ties to Eli Lilly, Gelesis, GI Dynamics, IntelliHealth, Johnson & Johnson, Novo Nordisk, Pfizer, and Rhythm Pharmaceuticals. Dr. Ryan has ties to numerous Novo Nordisk, Pfizer, and several other pharmaceutical companies, including having an ownership interest in Gila Therapeutics, Xeno Biosciences, Epitomee, Calibrate, Roman, and Scientific Intake.

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

“When considering the challenges of obesity, ask yourself: ‘If it were diabetes, cancer, HIV, or Alzheimer’s, how would you discuss it, approach it, assess it, treat it?’” Lee M. Kaplan, MD, PhD, asked the audience of health care professionals during ObesityWeek®, the annual meeting of The Obesity Society.

“And then do it for obesity, using the full spectrum of tools at our disposal,” he advised.

This was the takeaway that Dr. Kaplan, director of the Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital and associate professor, Harvard Medical School, Boston, left the audience with at the end of his lecture entitled, “What does the future of obesity care look like?”

Invited to summarize his main points, Dr. Kaplan told this news organization in an interview that practitioners caring for patients with obesity need to first “recognize that obesity is a disease” caused by dysfunction of the metabolic system that regulates body fat – in the same way immune dysregulation can lead to asthma.

Second, “we are finally developing noninvasive therapies that are more effective,” he noted, referring to the recently approved semaglutide, and even more potent weight-loss therapies that could be on the market within 3 years, so that weight-loss outcomes with pharmacotherapy are approaching those with bariatric surgery.

Third, it is important that patients with obesity get “broad and equitable access” to treatment, and health care practitioners need to be on the same page and have a “shared understanding” of which treatments are appropriate for individual patients, “just as we do for other diseases.”  
 

Need for a shared understanding

“Dr. Kaplan really brought home the idea that we all need a shared understanding of what obesity is – and what it is not,” agreed symposium moderator Donna H. Ryan, MD, in an email.

“He underscored the biologic basis of obesity,” noted Dr. Ryan, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana, and associate editor-in-chief of Obesity, the official journal of The Obesity Society.

“It is a dysregulation of the body’s weight (especially adipose tissue) regulatory system,” she continued. “The body responds to powerful environmental pressures that produce excess energy balance, and we store that as fat and defend our highest fat mass. This makes obesity a disease, a chronic disease that requires a medical approach to reverse. It’s not a cosmetic problem, it’s a medical problem,” she emphasized.

There is so much misinformation out there about obesity, according to Dr. Ryan.

“People think it’s a lack of willpower, and even patients blame themselves for not being able to lose weight and keep it off. It’s not their fault! It’s biology.”

Although the supplement industry and fad diets falsely promise fast results, there is no magic diet, she continued.

“But we have made progress based on understanding the biologic basis of obesity and have new medications that offer real hope for patients.” 

“With 42% of U.S. adults having a BMI that qualifies as obesity, we need a concerted and broad effort to address this problem, and that starts with everybody on the same page as to what obesity is ... a shared understanding of the biologic basis of obesity. It’s time to take obesity seriously,” she summarized, echoing Dr. Kaplan.
 

A question of biology

“Obesity results from inappropriate pathophysiological regulation of body fat mass,” when the body defends adiposity, Dr. Kaplan explained at the start of his lecture.

The treatment strategy for obesity has always been a stepwise approach starting with lifestyle changes, then pharmacotherapy, then possibly bariatric surgery – each step with a potentially greater chance of weight loss. But now, he explained, medicine is on the verge of having an armamentarium of more potent weight-loss medications.

Compared with phentermine/topiramate, orlistat, naltrexone/bupropion, and liraglutide – which roughly might provide 5% to 10% weight loss, the glucagon-like peptide-1 (GLP-1) agonist semaglutide 2.4 mg/week (Wegovy, Novo Nordisk), approved by the U.S. Food and Drug Association in June, provides almost double this potential weight loss.

And two new agents that could provide “never seen before weight loss” of 25% could potentially enter the marketplace by 2025: the amylin agonist cagrilintide (Novo Nordisk) and the twincretin tirzepatide (Eli Lilly) (a combined glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 receptor agonist).

In addition, when liraglutide comes off patent, a generic version could potentially be introduced, and combined generic liraglutide plus generic phentermine/topiramate could be a less expensive weight-loss treatment option in the future, he noted.
 

One size does not fit all

Importantly, weight loss varies widely among individual patients.

A graph of potential weight loss with different treatments (for example, bariatric surgery or liraglutide) versus the percentage of patients that attain the weight losses is roughly bell-shaped, Dr. Kaplan explained. For example, in the STEP1 trial of semaglutide, roughly 7.1% of patients lost less than 5% of their initial weight, 25% of patients lost 20% to 30%, and 10.8% of patients lost 30% or more; that is, patients at the higher end had weight loss comparable to that seen with bariatric surgery

Adding pharmacotherapy after bariatric surgery could be synergistic. For example, in the GRAVITAS study of patients with type 2 diabetes who had gastric bypass surgery, those who received liraglutide after surgery had augmented weight loss compared with those who received placebo.

People at a cocktail party might come up to him and say, “I’d like to lose 5 pounds, 10 pounds,” Dr. Kaplan related in the Q&A session.

“That’s not obesity,” he emphasized. Obesity is excess body fat that poses a risk to health. A person with obesity may have 50 or more excess pounds, and the body is trying to defend this weight.

“If we want to treat obesity more effectively, we have to fully understand why it is a disease and how that disease differs from the cultural desire for thinness,” he reiterated.

“We have to keep the needs and goals of all people living with obesity foremost in our minds, even if many of them have been previously misled by the bias, stigma, blame, and discrimination that surrounds them.”

“We need to re-evaluate what we think we know about obesity and open our minds to new ideas,” he added.

Dr. Kaplan has reported financial ties to Eli Lilly, Gelesis, GI Dynamics, IntelliHealth, Johnson & Johnson, Novo Nordisk, Pfizer, and Rhythm Pharmaceuticals. Dr. Ryan has ties to numerous Novo Nordisk, Pfizer, and several other pharmaceutical companies, including having an ownership interest in Gila Therapeutics, Xeno Biosciences, Epitomee, Calibrate, Roman, and Scientific Intake.

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

“When considering the challenges of obesity, ask yourself: ‘If it were diabetes, cancer, HIV, or Alzheimer’s, how would you discuss it, approach it, assess it, treat it?’” Lee M. Kaplan, MD, PhD, asked the audience of health care professionals during ObesityWeek®, the annual meeting of The Obesity Society.

“And then do it for obesity, using the full spectrum of tools at our disposal,” he advised.

This was the takeaway that Dr. Kaplan, director of the Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital and associate professor, Harvard Medical School, Boston, left the audience with at the end of his lecture entitled, “What does the future of obesity care look like?”

Invited to summarize his main points, Dr. Kaplan told this news organization in an interview that practitioners caring for patients with obesity need to first “recognize that obesity is a disease” caused by dysfunction of the metabolic system that regulates body fat – in the same way immune dysregulation can lead to asthma.

Second, “we are finally developing noninvasive therapies that are more effective,” he noted, referring to the recently approved semaglutide, and even more potent weight-loss therapies that could be on the market within 3 years, so that weight-loss outcomes with pharmacotherapy are approaching those with bariatric surgery.

Third, it is important that patients with obesity get “broad and equitable access” to treatment, and health care practitioners need to be on the same page and have a “shared understanding” of which treatments are appropriate for individual patients, “just as we do for other diseases.”  
 

Need for a shared understanding

“Dr. Kaplan really brought home the idea that we all need a shared understanding of what obesity is – and what it is not,” agreed symposium moderator Donna H. Ryan, MD, in an email.

“He underscored the biologic basis of obesity,” noted Dr. Ryan, professor emerita at Pennington Biomedical Research Center in Baton Rouge, Louisiana, and associate editor-in-chief of Obesity, the official journal of The Obesity Society.

“It is a dysregulation of the body’s weight (especially adipose tissue) regulatory system,” she continued. “The body responds to powerful environmental pressures that produce excess energy balance, and we store that as fat and defend our highest fat mass. This makes obesity a disease, a chronic disease that requires a medical approach to reverse. It’s not a cosmetic problem, it’s a medical problem,” she emphasized.

There is so much misinformation out there about obesity, according to Dr. Ryan.

“People think it’s a lack of willpower, and even patients blame themselves for not being able to lose weight and keep it off. It’s not their fault! It’s biology.”

Although the supplement industry and fad diets falsely promise fast results, there is no magic diet, she continued.

“But we have made progress based on understanding the biologic basis of obesity and have new medications that offer real hope for patients.” 

“With 42% of U.S. adults having a BMI that qualifies as obesity, we need a concerted and broad effort to address this problem, and that starts with everybody on the same page as to what obesity is ... a shared understanding of the biologic basis of obesity. It’s time to take obesity seriously,” she summarized, echoing Dr. Kaplan.
 

A question of biology

“Obesity results from inappropriate pathophysiological regulation of body fat mass,” when the body defends adiposity, Dr. Kaplan explained at the start of his lecture.

The treatment strategy for obesity has always been a stepwise approach starting with lifestyle changes, then pharmacotherapy, then possibly bariatric surgery – each step with a potentially greater chance of weight loss. But now, he explained, medicine is on the verge of having an armamentarium of more potent weight-loss medications.

Compared with phentermine/topiramate, orlistat, naltrexone/bupropion, and liraglutide – which roughly might provide 5% to 10% weight loss, the glucagon-like peptide-1 (GLP-1) agonist semaglutide 2.4 mg/week (Wegovy, Novo Nordisk), approved by the U.S. Food and Drug Association in June, provides almost double this potential weight loss.

And two new agents that could provide “never seen before weight loss” of 25% could potentially enter the marketplace by 2025: the amylin agonist cagrilintide (Novo Nordisk) and the twincretin tirzepatide (Eli Lilly) (a combined glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 receptor agonist).

In addition, when liraglutide comes off patent, a generic version could potentially be introduced, and combined generic liraglutide plus generic phentermine/topiramate could be a less expensive weight-loss treatment option in the future, he noted.
 

One size does not fit all

Importantly, weight loss varies widely among individual patients.

A graph of potential weight loss with different treatments (for example, bariatric surgery or liraglutide) versus the percentage of patients that attain the weight losses is roughly bell-shaped, Dr. Kaplan explained. For example, in the STEP1 trial of semaglutide, roughly 7.1% of patients lost less than 5% of their initial weight, 25% of patients lost 20% to 30%, and 10.8% of patients lost 30% or more; that is, patients at the higher end had weight loss comparable to that seen with bariatric surgery

Adding pharmacotherapy after bariatric surgery could be synergistic. For example, in the GRAVITAS study of patients with type 2 diabetes who had gastric bypass surgery, those who received liraglutide after surgery had augmented weight loss compared with those who received placebo.

People at a cocktail party might come up to him and say, “I’d like to lose 5 pounds, 10 pounds,” Dr. Kaplan related in the Q&A session.

“That’s not obesity,” he emphasized. Obesity is excess body fat that poses a risk to health. A person with obesity may have 50 or more excess pounds, and the body is trying to defend this weight.

“If we want to treat obesity more effectively, we have to fully understand why it is a disease and how that disease differs from the cultural desire for thinness,” he reiterated.

“We have to keep the needs and goals of all people living with obesity foremost in our minds, even if many of them have been previously misled by the bias, stigma, blame, and discrimination that surrounds them.”

“We need to re-evaluate what we think we know about obesity and open our minds to new ideas,” he added.

Dr. Kaplan has reported financial ties to Eli Lilly, Gelesis, GI Dynamics, IntelliHealth, Johnson & Johnson, Novo Nordisk, Pfizer, and Rhythm Pharmaceuticals. Dr. Ryan has ties to numerous Novo Nordisk, Pfizer, and several other pharmaceutical companies, including having an ownership interest in Gila Therapeutics, Xeno Biosciences, Epitomee, Calibrate, Roman, and Scientific Intake.

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