As a member of the AGA, you understand the physical, emotional, and financial costs of digestive diseases. And you understand the tremendous value of research to advance patient care.

We are in a time of major scientific breakthroughs; however, there is a growing gap in federal funding for research. Without gastroenterology and hepatology research, there would be no discoveries to develop new diagnostic and therapeutic approaches and to improve our understanding of the pathogenesis of digestive diseases.

The AGA Research Foundation funds promising GI investigators who don’t receive funding at crucial times in their early careers. The research of these talented individuals, while important to the field, could end prematurely if they are left unfunded. That’s something the fields of gastroenterology and hepatology can’t afford, and that’s why, as an AGA member, I’m making a year-end donation to the AGA Research Foundation. You can help fill the funding gap and protect the next generation of investigators by joining me in supporting the AGA Research Foundation through a personal year-end gift.

Gifts to the AGA Research Foundation this past year directly supported 71 investigators. Despite this success, close to 245 other promising research proposals were not funded.

We must continue to foster the careers of talented scientists and clinicians, and protect the GI research pipeline. A financial contribution to the AGA Research Foundation is the opportunity for you to help foster the careers of talented scientists and protect the GI research pipeline.

Help make a difference. You can make your tax-deductible donation online at www.gastro.org/donateonline; by phone at 301-222-4002; or, by mail:

AGA Research Foundation
4930 Del Ray Avenue
Bethesda, MD 20814

All gifts are tax-deductible to the fullest extent of U.S. law.

Thank you for your support and best wishes for a happy, healthy holiday season and prosperous New Year.

As a member of the AGA, you understand the physical, emotional, and financial costs of digestive diseases. And you understand the tremendous value of research to advance patient care.

We are in a time of major scientific breakthroughs; however, there is a growing gap in federal funding for research. Without gastroenterology and hepatology research, there would be no discoveries to develop new diagnostic and therapeutic approaches and to improve our understanding of the pathogenesis of digestive diseases.

The AGA Research Foundation funds promising GI investigators who don’t receive funding at crucial times in their early careers. The research of these talented individuals, while important to the field, could end prematurely if they are left unfunded. That’s something the fields of gastroenterology and hepatology can’t afford, and that’s why, as an AGA member, I’m making a year-end donation to the AGA Research Foundation. You can help fill the funding gap and protect the next generation of investigators by joining me in supporting the AGA Research Foundation through a personal year-end gift.

Gifts to the AGA Research Foundation this past year directly supported 71 investigators. Despite this success, close to 245 other promising research proposals were not funded.

We must continue to foster the careers of talented scientists and clinicians, and protect the GI research pipeline. A financial contribution to the AGA Research Foundation is the opportunity for you to help foster the careers of talented scientists and protect the GI research pipeline.

Help make a difference. You can make your tax-deductible donation online at www.gastro.org/donateonline; by phone at 301-222-4002; or, by mail:

AGA Research Foundation
4930 Del Ray Avenue
Bethesda, MD 20814

All gifts are tax-deductible to the fullest extent of U.S. law.

Thank you for your support and best wishes for a happy, healthy holiday season and prosperous New Year.

As a member of the AGA, you understand the physical, emotional, and financial costs of digestive diseases. And you understand the tremendous value of research to advance patient care.

We are in a time of major scientific breakthroughs; however, there is a growing gap in federal funding for research. Without gastroenterology and hepatology research, there would be no discoveries to develop new diagnostic and therapeutic approaches and to improve our understanding of the pathogenesis of digestive diseases.

The AGA Research Foundation funds promising GI investigators who don’t receive funding at crucial times in their early careers. The research of these talented individuals, while important to the field, could end prematurely if they are left unfunded. That’s something the fields of gastroenterology and hepatology can’t afford, and that’s why, as an AGA member, I’m making a year-end donation to the AGA Research Foundation. You can help fill the funding gap and protect the next generation of investigators by joining me in supporting the AGA Research Foundation through a personal year-end gift.

Gifts to the AGA Research Foundation this past year directly supported 71 investigators. Despite this success, close to 245 other promising research proposals were not funded.

We must continue to foster the careers of talented scientists and clinicians, and protect the GI research pipeline. A financial contribution to the AGA Research Foundation is the opportunity for you to help foster the careers of talented scientists and protect the GI research pipeline.

Help make a difference. You can make your tax-deductible donation online at www.gastro.org/donateonline; by phone at 301-222-4002; or, by mail:

AGA Research Foundation
4930 Del Ray Avenue
Bethesda, MD 20814

All gifts are tax-deductible to the fullest extent of U.S. law.

Thank you for your support and best wishes for a happy, healthy holiday season and prosperous New Year.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

TOPLINE:

Patients with breast cancer who have low levels of vitamin D when they begin treatment with paclitaxel are more likely to develop peripheral neuropathy, suggesting that correcting levels before treatment might help prevent the condition.

METHODOLOGY:

• Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
• To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
• Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.

TAKEAWAY:

• Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
• The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
• The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).

IN PRACTICE:

The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.

SOURCE:

The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.

LIMITATIONS:

The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.

DISCLOSURES:

The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.

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

TOPLINE:

Patients with breast cancer who have low levels of vitamin D when they begin treatment with paclitaxel are more likely to develop peripheral neuropathy, suggesting that correcting levels before treatment might help prevent the condition.

METHODOLOGY:

• Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
• To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
• Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.

TAKEAWAY:

• Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
• The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
• The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).

IN PRACTICE:

The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.

SOURCE:

The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.

LIMITATIONS:

The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.

DISCLOSURES:

The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.

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

TOPLINE:

Patients with breast cancer who have low levels of vitamin D when they begin treatment with paclitaxel are more likely to develop peripheral neuropathy, suggesting that correcting levels before treatment might help prevent the condition.

METHODOLOGY:

• Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
• To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
• Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.

TAKEAWAY:

• Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
• The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
• The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).

IN PRACTICE:

The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.

SOURCE:

The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.

LIMITATIONS:

The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.

DISCLOSURES:

The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.

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

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

Epilepsy affects over 50 million people worldwide, making it one of the most common neurologic disorders. Though current antiseizure medications can control seizures in two-thirds of patients, drug-resistant epilepsy remains a major challenge for the remaining one-third, as does the lack of disease-modifying therapies.

But RNA-based therapeutics offer new hope, and experts predict they could fill these gaps and revolutionize epilepsy treatment.

“Current medicines for epilepsy are barely scraping the surface of what could be targeted. RNA therapeutics is going to change everything. It opens up entirely new targets – virtually anything in our genome becomes ‘druggable,’ ” said David Henshall, PhD, Royal College of Surgeons Ireland, Dublin.

Edward Kaye, MD, a pediatric neurologist and CEO of Stoke Therapeutics, agrees. “RNA therapeutics open up possibilities that could not have been imagined when I started my career,” he said in an interview.

“We now have the potential to change the way genetic epilepsies are treated by addressing the underlying genetic cause of the disease instead of just the seizures,” Dr. Kaye said.
 

Thank COVID?

Henrik Klitgaard, PhD, and Sakari Kauppinen, PhD, scientific co-founders of NEUmiRNA Therapeutics, noted that the success of messenger RNA (mRNA) vaccines to counter the COVID-19 pandemic has fueled interest in exploring the potential of RNA-based therapies as a new modality in epilepsy with improved therapeutic properties.

Dr. Klitgaard and Dr. Kauppinen recently co-authored a “critical review” on RNA therapies for epilepsy published online in Epilepsia.

Unlike current antiseizure medications, which only target ion channels and receptors, RNA therapeutics can directly intervene at the genetic level.

RNA drugs can be targeted toward noncoding RNAs, such as microRNAs, or toward mRNA. Targeting noncoding RNAs shows promise in sporadic, nongenetic epilepsies, and targeting of mRNAs shows promise in childhood monogenic epilepsies.

Preclinical studies have highlighted the potential of RNA therapies for treatment of epilepsy.

“At NEUmiRNA Therapeutics, we have successfully designed potent and selective RNA drugs for a novel disease target that enable unprecedented elimination of the drug resistance and chronic epilepsy in a preclinical model mimicking temporal lobe epilepsy,” said Dr. Klitgaard.

“Interestingly,” he said, “these experiments also showed a disappearance of symptoms for epilepsy that outlasted drug exposure, suggesting significant disease-modifying properties with a curative potential for epilepsy.”
 

Hope for Dravet syndrome

Currently, there is significant interest in development of antisense oligonucleotides (ASOs), particularly for Dravet syndrome, a rare genetic epileptic encephalopathy that begins in infancy and gives rise to seizures that don’t respond well to seizure medications.

Stoke Therapeutics is developing antisense therapies aimed at correcting mutations in sodium channel genes, which cause up to 80% of cases of Dravet syndrome.

The company recently reported positive safety and efficacy data from patients treated with STK-001, a proprietary ASO, in the two ongoing phase 1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label extension study.

“These new data suggest clinical benefit for patients 2-18 years of age treated with multiple doses of STK-001. The observed reductions in convulsive seizure frequency as well as substantial improvements in cognition and behavior support the potential for disease modification in a highly refractory patient population,” the company said in a news release.

Dr. Kaye noted that the company anticipates reporting additional data in the first quarter of 2024 and expects to provide an update on phase 3 planning in the first half of 2024.

“Twenty-five years ago, when I was caring for patients in my clinic, half of epilepsy was considered idiopathic because we didn’t know the cause,” Dr. Kaye commented.

“Since then, thanks to an understanding of the genetics and more widely available access to genetic testing, we can determine the root cause of most of them. Today, I believe we are on the verge of a fundamental shift in how we approach the treatment of Dravet syndrome and, hopefully, other genetic epilepsies,” said Dr. Kaye.

“We are now finally getting to the point that we not only know the causes, but we are in a position to develop medicines that target those causes. We have seen this happen in other diseases like cystic fibrosis, and the time has come for genetic epilepsies,” he added.
 

A promising future

Dr. Henshall said that the ability to target the cause rather than just the symptoms of epilepsy “offers the promise of disease-modifying and potentially curative medicines in the future.”

And what’s exciting is that the time frame of developing RNA medicines may be “radically” different than it is for traditional small-drug development, he noted.

Take, for example, a case reported recently in the New England Journal of Medicine.

Researchers identified a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (a form of Batten’s disease), a rare and fatal neurodegenerative disease. Identification of the mutation was followed by the development and use (within 1 year) of a tailored RNA drug to treat the patient.

One downside perhaps is that current RNA drugs for epilepsy are delivered intrathecally, which is different from oral administration of small-molecule drugs.

However, Dr. Kauppinen from NEUmiRNA Therapeutics noted that “advances in intrathecal delivery technologies [and] the frequent use of this route of administration in other diseases and IT administration only being required two to three times per year will certainly facilitate use of RNA medicines.”

“This will also eliminate the issue of drug adherence by ensuring full patient compliance to treatment,” Dr. Kauppinen said.

The review article on RNA therapies in epilepsy had no commercial funding. Dr. Henshall holds a patent and has filed intellectual property related to microRNA targeting therapies for epilepsy and has received funding for microRNA research from NEUmiRNA Therapeutics. Dr. Klitgaard and Dr. Kauppinen are cofounders of NEUmiRNA Therapeutics. Dr. Kaye is CEO of Stoke Therapeutics.

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

This transcript has been edited for clarity.

Today we are going to talk about the American Geriatrics Society 2023 updated Beers Criteria guidance for medication use in older adults. These criteria have been updated and revised approximately every 5 years since 1991 and serve to alert us to medications for which the risk-benefit ratio is not as good in older adults as in the rest of the population.

These are important criteria because medications are metabolized differently in older adults and have different effects compared with younger patients. For the sake of these criteria, older adults are 65 years of age or older. That said, we know that everyone from 65 to 100 is not the same. As people age, they develop more comorbidities, they become more frail, and they are more sensitive to the effects and side effects of drugs.

The guidance covers potentially inappropriate medications for older adults. The word “potentially” is important because this is guidance. As clinicians, we make decisions involving individuals. This guidance should be used with judgment, integrating the clinical context of the individual patient.

There is a lot in this guidance. I am going to try to cover what I feel are the most important points.

Aspirin. Since the risk for major bleeding increases with age, for primary prevention of atherosclerotic cardiovascular disease, the harm can be greater than the benefit in older adults, so aspirin should not be used for primary prevention. Aspirin remains indicated for secondary prevention in individuals with established cardiovascular disease.

Warfarin. For treatment of atrial fibrillation or venous thromboembolism (deep vein thrombosis or pulmonary embolism), warfarin should be avoided if possible. Warfarin has a higher risk for major bleeding, particularly intracranial bleeding, than direct oral anticoagulants (DOACs); therefore the latter are preferred. Rivaroxaban should be avoided, as it has a higher risk for major bleeding in older adults than the other DOACs. Apixaban is preferred over dabigatran. If a patient is well controlled on warfarin, you can consider continuing that treatment.

Antipsychotics. These include first- and second-generation antipsychotics such as aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and others. The guidance says to avoid these agents except for FDA-approved indications such as schizophrenia, bipolar disorder, and adjuvant treatment of depression. Use of these antipsychotics can increase risk for stroke, heart attack, and mortality. Essentially, the guidance says do not use these medications lightly for the treatment of agitated dementia. For those of us with older patients, this can get tricky because agitated dementia is a difficult issue for which there are no good effective medications. The Beers guidance recognizes this in saying that these medications should be avoided unless behavioral interventions have failed. So, there are times where you may need to use these medicines, but use them judiciously.

For patients with dementia, anticholinergics, antipsychotics, and benzodiazepines should be avoided if possible.

Benzodiazepines. Benzodiazepines should also be avoided because older adults have increased sensitivity to their effects due to slower metabolism and clearance of these medications, which can lead to a much longer half-life and higher serum level. In older adults, benzodiazepines increase the risk for cognitive impairment, delirium, falls, fractures, and even motor accidents. The same concerns affect the group of non-benzodiazepine sleeping medicines known as “Z-drugs.”

Nonsteroidal anti-inflammatory drugs (NSAIDs). Used frequently in our practices, NSAIDs are nevertheless on the list. As we think through the risk-benefit ratio of using NSAIDs in older adults, we often underappreciate the risks of these agents. Upper gastrointestinal ulcers with bleeding occur in approximately 1% of patients treated for 3-6 months with an NSAID and in 2%-4% of patients treated for a year. NSAIDs also increase the risk for renal impairment and cardiovascular disease.

Other medications to avoid (if possible). These include:

Sulfonylureas, due to a high risk for hypoglycemia. A short-acting sulfonylurea, such as glipizide, should be used if one is needed.

Proton pump inhibitors should not be used long-term if it can be avoided.

Digoxin should not be first-line treatment for atrial fibrillation or heart failure. Decreased renal clearance in older adults can lead to toxic levels of digoxin, particularly during acute illnesses. Avoid doses > 0.125 mg/day.

Nitrofurantoin should be avoided when the patient’s creatinine clearance is < 30 or for long-term suppressive therapy.

Avoid combining medications that have high anticholinergic side effects, such as scopolamine, diphenhydramine, oxybutynin, cyclobenzaprine, and others.

It is always important to understand the benefits and the risks of the drugs we prescribe. It is also important to remember that older adults are a particularly vulnerable population. The Beers criteria provide important guidance, which we can then use to make decisions about medicines for individual patients.

Dr. Skolnik is a professor in the department of family medicine at Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, and associate director in the department of family medicine at Abington (Pa.) Jefferson Health. He disclosed ties with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GSK, Merck, Sanofi, Sanofi Pasteur, and Teva.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Today we are going to talk about the American Geriatrics Society 2023 updated Beers Criteria guidance for medication use in older adults. These criteria have been updated and revised approximately every 5 years since 1991 and serve to alert us to medications for which the risk-benefit ratio is not as good in older adults as in the rest of the population.

These are important criteria because medications are metabolized differently in older adults and have different effects compared with younger patients. For the sake of these criteria, older adults are 65 years of age or older. That said, we know that everyone from 65 to 100 is not the same. As people age, they develop more comorbidities, they become more frail, and they are more sensitive to the effects and side effects of drugs.

The guidance covers potentially inappropriate medications for older adults. The word “potentially” is important because this is guidance. As clinicians, we make decisions involving individuals. This guidance should be used with judgment, integrating the clinical context of the individual patient.

There is a lot in this guidance. I am going to try to cover what I feel are the most important points.

Aspirin. Since the risk for major bleeding increases with age, for primary prevention of atherosclerotic cardiovascular disease, the harm can be greater than the benefit in older adults, so aspirin should not be used for primary prevention. Aspirin remains indicated for secondary prevention in individuals with established cardiovascular disease.

Warfarin. For treatment of atrial fibrillation or venous thromboembolism (deep vein thrombosis or pulmonary embolism), warfarin should be avoided if possible. Warfarin has a higher risk for major bleeding, particularly intracranial bleeding, than direct oral anticoagulants (DOACs); therefore the latter are preferred. Rivaroxaban should be avoided, as it has a higher risk for major bleeding in older adults than the other DOACs. Apixaban is preferred over dabigatran. If a patient is well controlled on warfarin, you can consider continuing that treatment.

Antipsychotics. These include first- and second-generation antipsychotics such as aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and others. The guidance says to avoid these agents except for FDA-approved indications such as schizophrenia, bipolar disorder, and adjuvant treatment of depression. Use of these antipsychotics can increase risk for stroke, heart attack, and mortality. Essentially, the guidance says do not use these medications lightly for the treatment of agitated dementia. For those of us with older patients, this can get tricky because agitated dementia is a difficult issue for which there are no good effective medications. The Beers guidance recognizes this in saying that these medications should be avoided unless behavioral interventions have failed. So, there are times where you may need to use these medicines, but use them judiciously.

For patients with dementia, anticholinergics, antipsychotics, and benzodiazepines should be avoided if possible.

Benzodiazepines. Benzodiazepines should also be avoided because older adults have increased sensitivity to their effects due to slower metabolism and clearance of these medications, which can lead to a much longer half-life and higher serum level. In older adults, benzodiazepines increase the risk for cognitive impairment, delirium, falls, fractures, and even motor accidents. The same concerns affect the group of non-benzodiazepine sleeping medicines known as “Z-drugs.”

Nonsteroidal anti-inflammatory drugs (NSAIDs). Used frequently in our practices, NSAIDs are nevertheless on the list. As we think through the risk-benefit ratio of using NSAIDs in older adults, we often underappreciate the risks of these agents. Upper gastrointestinal ulcers with bleeding occur in approximately 1% of patients treated for 3-6 months with an NSAID and in 2%-4% of patients treated for a year. NSAIDs also increase the risk for renal impairment and cardiovascular disease.

Other medications to avoid (if possible). These include:

Sulfonylureas, due to a high risk for hypoglycemia. A short-acting sulfonylurea, such as glipizide, should be used if one is needed.

Proton pump inhibitors should not be used long-term if it can be avoided.

Digoxin should not be first-line treatment for atrial fibrillation or heart failure. Decreased renal clearance in older adults can lead to toxic levels of digoxin, particularly during acute illnesses. Avoid doses > 0.125 mg/day.

Nitrofurantoin should be avoided when the patient’s creatinine clearance is < 30 or for long-term suppressive therapy.

Avoid combining medications that have high anticholinergic side effects, such as scopolamine, diphenhydramine, oxybutynin, cyclobenzaprine, and others.

It is always important to understand the benefits and the risks of the drugs we prescribe. It is also important to remember that older adults are a particularly vulnerable population. The Beers criteria provide important guidance, which we can then use to make decisions about medicines for individual patients.

Dr. Skolnik is a professor in the department of family medicine at Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, and associate director in the department of family medicine at Abington (Pa.) Jefferson Health. He disclosed ties with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GSK, Merck, Sanofi, Sanofi Pasteur, and Teva.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Today we are going to talk about the American Geriatrics Society 2023 updated Beers Criteria guidance for medication use in older adults. These criteria have been updated and revised approximately every 5 years since 1991 and serve to alert us to medications for which the risk-benefit ratio is not as good in older adults as in the rest of the population.

These are important criteria because medications are metabolized differently in older adults and have different effects compared with younger patients. For the sake of these criteria, older adults are 65 years of age or older. That said, we know that everyone from 65 to 100 is not the same. As people age, they develop more comorbidities, they become more frail, and they are more sensitive to the effects and side effects of drugs.

The guidance covers potentially inappropriate medications for older adults. The word “potentially” is important because this is guidance. As clinicians, we make decisions involving individuals. This guidance should be used with judgment, integrating the clinical context of the individual patient.

There is a lot in this guidance. I am going to try to cover what I feel are the most important points.

Aspirin. Since the risk for major bleeding increases with age, for primary prevention of atherosclerotic cardiovascular disease, the harm can be greater than the benefit in older adults, so aspirin should not be used for primary prevention. Aspirin remains indicated for secondary prevention in individuals with established cardiovascular disease.

Warfarin. For treatment of atrial fibrillation or venous thromboembolism (deep vein thrombosis or pulmonary embolism), warfarin should be avoided if possible. Warfarin has a higher risk for major bleeding, particularly intracranial bleeding, than direct oral anticoagulants (DOACs); therefore the latter are preferred. Rivaroxaban should be avoided, as it has a higher risk for major bleeding in older adults than the other DOACs. Apixaban is preferred over dabigatran. If a patient is well controlled on warfarin, you can consider continuing that treatment.

Antipsychotics. These include first- and second-generation antipsychotics such as aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and others. The guidance says to avoid these agents except for FDA-approved indications such as schizophrenia, bipolar disorder, and adjuvant treatment of depression. Use of these antipsychotics can increase risk for stroke, heart attack, and mortality. Essentially, the guidance says do not use these medications lightly for the treatment of agitated dementia. For those of us with older patients, this can get tricky because agitated dementia is a difficult issue for which there are no good effective medications. The Beers guidance recognizes this in saying that these medications should be avoided unless behavioral interventions have failed. So, there are times where you may need to use these medicines, but use them judiciously.

For patients with dementia, anticholinergics, antipsychotics, and benzodiazepines should be avoided if possible.

Benzodiazepines. Benzodiazepines should also be avoided because older adults have increased sensitivity to their effects due to slower metabolism and clearance of these medications, which can lead to a much longer half-life and higher serum level. In older adults, benzodiazepines increase the risk for cognitive impairment, delirium, falls, fractures, and even motor accidents. The same concerns affect the group of non-benzodiazepine sleeping medicines known as “Z-drugs.”

Nonsteroidal anti-inflammatory drugs (NSAIDs). Used frequently in our practices, NSAIDs are nevertheless on the list. As we think through the risk-benefit ratio of using NSAIDs in older adults, we often underappreciate the risks of these agents. Upper gastrointestinal ulcers with bleeding occur in approximately 1% of patients treated for 3-6 months with an NSAID and in 2%-4% of patients treated for a year. NSAIDs also increase the risk for renal impairment and cardiovascular disease.

Other medications to avoid (if possible). These include:

Sulfonylureas, due to a high risk for hypoglycemia. A short-acting sulfonylurea, such as glipizide, should be used if one is needed.

Proton pump inhibitors should not be used long-term if it can be avoided.

Digoxin should not be first-line treatment for atrial fibrillation or heart failure. Decreased renal clearance in older adults can lead to toxic levels of digoxin, particularly during acute illnesses. Avoid doses > 0.125 mg/day.

Nitrofurantoin should be avoided when the patient’s creatinine clearance is < 30 or for long-term suppressive therapy.

Avoid combining medications that have high anticholinergic side effects, such as scopolamine, diphenhydramine, oxybutynin, cyclobenzaprine, and others.

It is always important to understand the benefits and the risks of the drugs we prescribe. It is also important to remember that older adults are a particularly vulnerable population. The Beers criteria provide important guidance, which we can then use to make decisions about medicines for individual patients.

Dr. Skolnik is a professor in the department of family medicine at Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, and associate director in the department of family medicine at Abington (Pa.) Jefferson Health. He disclosed ties with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GSK, Merck, Sanofi, Sanofi Pasteur, and Teva.

A version of this article appeared on Medscape.com.

Prior authorization requirements delay or preclude recommended treatment in a substantial proportion of oncology patients, findings from a survey-based cross-sectional study suggest.

Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.

Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.

Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.

The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.

“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”

To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.

PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).

“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.

PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.

Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.

The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.

“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.

“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.

Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.

Prior authorization requirements delay or preclude recommended treatment in a substantial proportion of oncology patients, findings from a survey-based cross-sectional study suggest.

Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.

Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.

Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.

The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.

“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”

To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.

PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).

“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.

PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.

Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.

The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.

“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.

“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.

Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.

Prior authorization requirements delay or preclude recommended treatment in a substantial proportion of oncology patients, findings from a survey-based cross-sectional study suggest.

Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.

Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.

Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.

The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.

“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”

To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.

PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).

“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.

PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.

Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.

The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.

“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.

“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.

Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.

Clinicians must monitor children with sickle cell disease for eye complications as much as they do for adults, a new research review suggests.

Earlier research indicated that older patients were more at risk for eye complications from sickle cell disease, but the new study found that a full third of young people aged 10-25 years with sickle cell disease had retinopathy, including nonproliferative retinopathy (33%) and proliferative retinopathy (6%), which can progress to vision loss.

Two patients experienced retinal detachment, while two suffered retinal artery occlusion. One patient with retinal artery occlusion lost their vision and had a final best-corrected visual acuity of 20/60, according to the researchers, who presented their findings at the annual meeting of the American Academy of Ophthalmology.

“Our data underscores the need for patients – including pediatric patients – with sickle cell disease to get routine ophthalmic screenings along with appropriate systemic and ophthalmic treatment,” Mary Ellen Hoehn, MD, a professor of ophthalmology at the University of Tennessee Health Science Center, Memphis, who led the research, said in a press release.

The review covered records for 652 patients with sickle cell disease aged 10-25 years (median age, 14 years), who underwent eye exams over a 12-year period.

Besides looking at rates of retinopathy, Dr. Hoehn’s group studied which treatments were most effective. They found that hydroxyurea and chronic transfusions best lowered retinopathy rates among all genotypes.

“We hope that people will use this information to better care for patients with sickle cell disease, and that more timely ophthalmic screen exams will be performed so that vision-threatening complications from this disease are prevented,” Dr. Hoehn said.

The authors reported no relevant financial relationships.

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

Clinicians must monitor children with sickle cell disease for eye complications as much as they do for adults, a new research review suggests.

Earlier research indicated that older patients were more at risk for eye complications from sickle cell disease, but the new study found that a full third of young people aged 10-25 years with sickle cell disease had retinopathy, including nonproliferative retinopathy (33%) and proliferative retinopathy (6%), which can progress to vision loss.

Two patients experienced retinal detachment, while two suffered retinal artery occlusion. One patient with retinal artery occlusion lost their vision and had a final best-corrected visual acuity of 20/60, according to the researchers, who presented their findings at the annual meeting of the American Academy of Ophthalmology.

“Our data underscores the need for patients – including pediatric patients – with sickle cell disease to get routine ophthalmic screenings along with appropriate systemic and ophthalmic treatment,” Mary Ellen Hoehn, MD, a professor of ophthalmology at the University of Tennessee Health Science Center, Memphis, who led the research, said in a press release.

The review covered records for 652 patients with sickle cell disease aged 10-25 years (median age, 14 years), who underwent eye exams over a 12-year period.

Besides looking at rates of retinopathy, Dr. Hoehn’s group studied which treatments were most effective. They found that hydroxyurea and chronic transfusions best lowered retinopathy rates among all genotypes.

“We hope that people will use this information to better care for patients with sickle cell disease, and that more timely ophthalmic screen exams will be performed so that vision-threatening complications from this disease are prevented,” Dr. Hoehn said.

The authors reported no relevant financial relationships.

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

Clinicians must monitor children with sickle cell disease for eye complications as much as they do for adults, a new research review suggests.

Earlier research indicated that older patients were more at risk for eye complications from sickle cell disease, but the new study found that a full third of young people aged 10-25 years with sickle cell disease had retinopathy, including nonproliferative retinopathy (33%) and proliferative retinopathy (6%), which can progress to vision loss.

Two patients experienced retinal detachment, while two suffered retinal artery occlusion. One patient with retinal artery occlusion lost their vision and had a final best-corrected visual acuity of 20/60, according to the researchers, who presented their findings at the annual meeting of the American Academy of Ophthalmology.

“Our data underscores the need for patients – including pediatric patients – with sickle cell disease to get routine ophthalmic screenings along with appropriate systemic and ophthalmic treatment,” Mary Ellen Hoehn, MD, a professor of ophthalmology at the University of Tennessee Health Science Center, Memphis, who led the research, said in a press release.

The review covered records for 652 patients with sickle cell disease aged 10-25 years (median age, 14 years), who underwent eye exams over a 12-year period.

Besides looking at rates of retinopathy, Dr. Hoehn’s group studied which treatments were most effective. They found that hydroxyurea and chronic transfusions best lowered retinopathy rates among all genotypes.

“We hope that people will use this information to better care for patients with sickle cell disease, and that more timely ophthalmic screen exams will be performed so that vision-threatening complications from this disease are prevented,” Dr. Hoehn said.

The authors reported no relevant financial relationships.

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

This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

This transcript has been edited for clarity.

I am far from the only doctor, and certainly far from the only oncologist, to recently comment on the topic of Maintenance of Certification. Of course, this is happening in a wider debate about our relationship as subspecialists to the American Board of Internal Medicine, and what they deem acceptable for the recertification of doctors in practice.

My take is that every oncologist is already engaged in lifelong learning. One of the things I tell my patients is that if I practiced exactly the way I was trained to practice — and I had a very good fellowship program with superb faculty – if I practiced the way they taught me, it would now be malpractice. I finished my fellowship in 2012, just over a decade ago. The rate of progress in the interim is simply staggering. It looks so different now than it did then.

For instance, 2011 was my first experience ever using a form of immunotherapy. It was an anti-CTLA4 agent, ipilimumab, and I was treating metastatic melanoma. I learned in that instance just how effective these drugs can be, but also how toxic they can be. Ever since then, I’ve been refining my use of immunotherapy. We do that iteratively. We do that as we encounter patients and as we try to meet their needs.

I do understand that the ABIM is saying they want an independent governing body to legislate that process. I think the reason this is stuck in the craw of so many oncologists is that we demonstrate our commitment to continuing medical education all the time.

I’m recording this in my office, which is separate from the space where I see patients. I see patients in a different group of exam rooms for their privacy and it’s a better setup for aspects of the physical encounter. Not a single patient has ever asked to come into my office and see my diplomas, and I sometimes wonder if I keep them here mostly as a visual cue to myself, sort of an antidote to ward off imposter syndrome and remind myself, Oh yeah – I earned these. I earned these through formal training.

Then something happens once you finish your training, whether it’s residency or fellowship, and you become an attending. I think you feel a weight of responsibility, the responsibility of independent learning. All of us are doing this. We have to do this. The field is moving along at such a rapid clip that it’s essentially built into what we do that we are going to keep up. In fact, channels such as the various aspects of social media are a way I curate my own information feed so I can stay up to speed and not feel like I’m drowning in a deluge of new data.

But what’s hard to demonstrate to the ABIM is that [this learning] is already happening. I think we can do it if we submit our records of CME credits that we formally accrue. The reason this is such an almost insult to oncologists in practice is because it is a necessary part of our day-to-day existence to keep apprised of developments so we can apply them to patient care.

One litmus test of attending a medical conference like the annual meeting of the American Society of Clinical Oncology is to ask oneself, When I go back to clinic, is this meeting going to change the way that I take care of patients? The answer almost invariably these days is yes. I go to multiple meetings per year, and I think it’s the exception, not the rule, that I return home and nothing changes in my management patterns. Again, this process is happening whether the ABIM recognizes it or not.

Lastly, I sat down in the fall of 2022 and I did my recertification. I looked at the span of all the things that had happened between 2012, when I first sat for my board examination in medical oncology, and 2022. It was staggering. I think the reason that it wasn’t such an overwhelming amount of information to review is that I had actually been accreting it slowly and gradually, month by month, year by year throughout that decade.

Again, it’s necessary that the ABIM hear us, hear oncologists, and know that of all the medical subspecialties they govern, it is basically already an essential task of our day-to-day professional existence that we engage in lifelong learning. To suggest otherwise really paints us as outdated. The reason that matters so much is that if we’re not up-to-date, then we are underserving our patients.

Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City. He reported no relevant conflicts of interest.

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

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.

“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.

“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”

A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.

The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.

Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
 

Anti-drug antibodies, genetics, other factors in psoriasis

Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”

A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).

“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.

He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.

“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.

In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.

The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.

Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.

In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.

The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).

The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.
 

Comorbidities and biologic failure in psoriasis, PsA

In practice, it was said during a discussion period, biologic failures in psoriasis can be of two types: a primary inadequate response or initial failure, or a secondary failure with initial improvement followed by declining or no response. “I agree 100% that these probably represent two different endotypes,” Dr. Liao said. “There’s research emerging that psoriasis isn’t necessarily a clean phenotype.”

The option of focusing on comorbidities in the face of biologic failure was another point of discussion. “Maybe the next biologic is not the answer,” a meeting participant said. “Maybe we should focus on metabolic syndrome.”

“I agree,” Dr. Liao said. “In clinic, there are people who may not respond to therapies but have other comorbidities and factors that make it difficult to manage [their psoriasis] ... that may be causative for psoriasis. Maybe if we treat the comorbidities, it will make it easier to treat the psoriasis.”

Addressing comorbidities and “extra-articular traits” such as poorly controlled diabetes, centralized pain, anxiety and depression, and obesity is something Dr. Ritchlin advocates for PsA. “Centralized pain, I believe, is a major driver of nonresponse,” he said at the meeting. “We have to be careful about blaming nonresponse and lack of efficacy of biologics when it could be a wholly different mechanism the biologic won’t treat ... for example, centralized pain.”

As with psoriasis, the emergence of antidrug antibodies may be one reason for the secondary failure of biologic agents for PsA, Dr. Ritchlin and his coauthors wrote in their paper on management of PsA after failure of one TNF inhibitor. Other areas to consider in evaluating failure, they wrote, are compliance and time of dosing, and financial barriers.

Low long-term persistence of second-line biologics for patients with PsA was demonstrated in a national cohort study utilizing the French health insurance database, Dr. Ritchlin noted at the research meeting. 

The French study covered almost 3,000 patients who started a second biologic after discontinuing a TNF inhibitor during 2015-2020. Overall, 1-year and 3-year persistence rates were 42% and 17%, respectively.

Dr. Liao disclosed research grant funding from AbbVie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and Trex Bio. Dr. Ritchlin reported no disclosures.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.

Knowing the sex of a developing fetus is a common question many expectant parents ask at their prenatal appointments. While the sex of a fetus has minimal clinical significance to obstetrician/gynecologists, technology has made ascertaining the answer to this question much more accessible.

In addition to detecting certain genetic abnormalities, both noninvasive prenatal testing (NIPT) and preimplantation genetic testing (PGT) can discern the chromosomal sex of a fetus prior to birth. At the 20-week anatomy scan, the ultrasonographer can detect the presence of external genitalia to determine the sex. In fact, when a baby is first born, obstetrician/gynecologists are consistently asked “do I have a boy or a girl?” Assigning the sex of a newborn is one of the many tasks we complete in the delivery room. However, some of you reading this article would disagree.

“You cannot assign sex at birth.” “Sex is fixed, you cannot change biology.” These are examples of statements that frequent the comments section of my medical articles and plague professionals who treat gender diverse patients. I would argue, as would many biologists, scientists, and physicians, that these statements oversimplify biologic reality.

The term “sex” has multiple meanings: It can allude to the act of reproduction itself, but in the context of sexual determination and sexual differentiation, it can refer to the biologic and structural composition of a developing human. Within this paradigm, there exist three definitions for sex: chromosomal, gonadal, and phenotypic.

Chromosomal sex refers to the genetic makeup of a human, typically XX or XY chromosomes. There are also variations within this seemingly binary system. Embryos can have an extra sex chromosome, as seen in Klinefelter syndrome, which is characterized by XXY karyotype. Embryos can also be devoid of a sex chromosome, as observed in Turner’s syndrome, which is characterized by an XO karyotype. These variations can impact fertility and expression of secondary sexual characteristics as the type of sex chromosomes present results in primary sex determination, or the development of gonads.

Most often, individuals with a chromosomal makeup of XX are considered female and will subsequently develop ovaries that produce oocytes (eggs). Individuals with XY chromosomes are deemed male and will go on to develop testes, which are responsible for spermatogenesis (sperm production).

Gonadal sex is the presence of either testes or ovaries. The primary function of testes is to produce sperm for reproduction and to secrete testosterone, the primary male sex hormone. Similarly, ovaries produce oocytes and secrete estrogen as the primary female sex hormone. Gonads can be surgically removed either via orchiectomy (the removal of testes), or oophorectomy (the removal of ovaries) for a variety of reasons. There is no current medical technology that can replace the function of these structures, although patients can be placed on hormone replacement to counter the negative physiologic consequences resulting from their removal.

Secondary sex determination, or sexual differentiation, is the development of external genitalia and internal genital tracts because of the hormones produced from the gonads. At puberty, further differentiation occurs with the development of pubic and axillary hair and breast growth. This process determines phenotypic sex – the visible distinction between male and female.

When opponents of gender affirming care state that individuals cannot change sex, are they correct or false? The answer to this question is entirely dependent on which definition of sex they are using. Chromosomal? Gonadal? Phenotypic? It is an immutable fact that humans cannot change chromosomal sex. No one in the transgender community, either provider or patient, would dispute this. However, we can remove gonadal structures and alter phenotypic sex.

The goal of gender affirming hormone therapy and surgery isn’t to change chromosomal sex, but to alter one’s phenotypic sex so the physical body a patient sees, and others see, is reflective of how the patient feels. In fact, many cisgender individuals also revise their phenotypic sex when they undergo augmentation mammaplasty, penile enlargement, or vulvoplasty procedures for the exact same reason.

Circling back to the debate about whether we can “assign sex at birth,” it all depends on what definition of sex you are referencing. At birth, obstetrician/gynecologists most often look at the phenotypic sex and make assumptions about the genetic and gonadal sex based on the secondary sexual characteristics. So yes, we can, and we do assign sex at birth. However, in the case of intersex individuals, these physical characteristics may not align with their gonadal and chromosomal composition.

In the case of an infant that has a known XY karyotype prior to birth but a female phenotype at birth (as seen in a condition called complete androgen insensitivity syndrome), what sex should be assigned to that baby? Should the infant be raised male or female? A lot of unintended but significant harm has resulted from providers and parents trying to answer that very question. The mistreatment of intersex patients through forced and coercive medical and surgical treatments, often in infancy, should serve as a dark reminder that sex and gender are not as biologically binary as we would like to believe.

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa. She has no relevant disclosures.

References

Moore KL and Persaud TVN. The urogenital system. In: Before we are born: essentials of embryology and birth defects. 7th ed. Philadelphia: Saunders Elsevier;2008:163-89.

Standring S. Development of the urogenital system. In: Gray’s Anatomy, 42nd ed. Philadelphia: Elsevier;2021:341-64.

Escobar O et al. Pediatric endocrinology. In: Zitelli BJ, ed. Zitelli and Davis’ atlas of pediatric physical diagnosis 8th edition. Philadelphia: Elsevier;2023:342-81.