Practice Gap

Orodynia (OD)—together with glossodynia colloquially termed “burning mouth syndrome”—is a chronic disorder characterized by a burning sensation within the oral cavity without objective clinical signs. It is most common in perimenopausal and postmenopausal women.^1,2

Orodynia is a diagnosis of exclusion and is considered after 4 to 6 months of normal imaging and laboratory test results.^1,2 Its pathophysiology is poorly understood, as it can be intermittent or continuous, manifest with a variety of symptoms, and affect various entities of the oral cavity.^3,4 The most common structure affected is the tongue, and symptoms may include xerostomia, dysgeusia, and discomfort.^1,2 Orodynia is a frustrating condition, as many patients do not respond to treatment and experience symptoms for years.^1-4

The current approach to management of OD typically involves a combination of psychosocial strategies and pharmacologic agents. The psychosocial component consists of coping mechanisms (eg, stress management techniques and behavioral therapies) aimed at alleviating the psychological impact of the condition. Pharmacologic agents such as antidepressants, anticonvulsants, and topical medications often are prescribed to address neuropathic pain and dry mouth symptoms.^1,2 Additionally, oral rinses, saliva substitutes, and dietary supplements may be recommended to counteract the discomfort associated with xerostomia.^1,2 However, there is no stepwise protocol, leaving these treatments to be trialed in a disorganized manner.²

The Tools

In our unique approach to managing OD, physicians may employ a variety of tools, including autoantibody profiles, noninvasive salivary gland analysis, saliva analysis, patch testing for allergens, and—if deemed necessary—a minor salivary gland biopsy. The use of specific prescription medications is included in the later stages of our approach.

The Technique

First, exclude inflammatory conditions such as geographic tongue, oral lichen planus, autoimmune bullous disorders, and other treatable conditions such as dyspepsia and Sjögren syndrome using the tools described above. Noninvasive modalities should be exhausted first, and dermatologists/clinicians should exercise clinical judgement to determine whether all options should be trialed, including more invasive/costly ones.

If symptoms persist, clinicians may want to obtain a culture for oral candida. If results are positive, candida may be treated quickly with oral fluconazole. If that treatment fails and fissuring is present, advise the patient on treating the tongue; we recommend lightly brushing the tongue once daily with a hydrogen peroxide 3% solution, followed by rinsing. Next, the patient can allow an active probiotic yogurt to sit on the tongue for at least 1 minute to repopulate it with healthy oral bacteria.

If symptoms persist, prescribe gabapentin 100 to 300 mg to be taken at bedtime. Cevimeline 30 mg 3 times daily can be added to treat symptoms of xerostomia. As a last resort, a low daily dose of trifluoperazine 1 to 2 mg may alleviate the dysesthesia of OD. Because this medication is an antipsychotic, there is an increased risk for adverse effects such as tardive dyskinesia; however, given that we recommend using at most one-twentieth of the dose recommended for psychiatric illnesses such as schizophrenia, the risk appears to be minimal.⁵

We have found this protocol to be more structured, and in our practice, it has led to better outcomes than previously described therapeutic interventions.

Practice Implications

As a chronic condition, OD can be frustrating for patients, as many of them have attempted multiple treatments without success. It also may be challenging for dermatologists who are unfamiliar with its management. This approach to OD provides simple step-by-step diagnostic and therapeutic plans for a condition with an often-uncertain etiology and stubborn response to initial treatments. By following this protocol, dermatologists can be confident in their ability to help patients find relief from OD.

Practice Gap

Orodynia (OD)—together with glossodynia colloquially termed “burning mouth syndrome”—is a chronic disorder characterized by a burning sensation within the oral cavity without objective clinical signs. It is most common in perimenopausal and postmenopausal women.^1,2

Orodynia is a diagnosis of exclusion and is considered after 4 to 6 months of normal imaging and laboratory test results.^1,2 Its pathophysiology is poorly understood, as it can be intermittent or continuous, manifest with a variety of symptoms, and affect various entities of the oral cavity.^3,4 The most common structure affected is the tongue, and symptoms may include xerostomia, dysgeusia, and discomfort.^1,2 Orodynia is a frustrating condition, as many patients do not respond to treatment and experience symptoms for years.^1-4

The current approach to management of OD typically involves a combination of psychosocial strategies and pharmacologic agents. The psychosocial component consists of coping mechanisms (eg, stress management techniques and behavioral therapies) aimed at alleviating the psychological impact of the condition. Pharmacologic agents such as antidepressants, anticonvulsants, and topical medications often are prescribed to address neuropathic pain and dry mouth symptoms.^1,2 Additionally, oral rinses, saliva substitutes, and dietary supplements may be recommended to counteract the discomfort associated with xerostomia.^1,2 However, there is no stepwise protocol, leaving these treatments to be trialed in a disorganized manner.²

The Tools

In our unique approach to managing OD, physicians may employ a variety of tools, including autoantibody profiles, noninvasive salivary gland analysis, saliva analysis, patch testing for allergens, and—if deemed necessary—a minor salivary gland biopsy. The use of specific prescription medications is included in the later stages of our approach.

The Technique

First, exclude inflammatory conditions such as geographic tongue, oral lichen planus, autoimmune bullous disorders, and other treatable conditions such as dyspepsia and Sjögren syndrome using the tools described above. Noninvasive modalities should be exhausted first, and dermatologists/clinicians should exercise clinical judgement to determine whether all options should be trialed, including more invasive/costly ones.

If symptoms persist, clinicians may want to obtain a culture for oral candida. If results are positive, candida may be treated quickly with oral fluconazole. If that treatment fails and fissuring is present, advise the patient on treating the tongue; we recommend lightly brushing the tongue once daily with a hydrogen peroxide 3% solution, followed by rinsing. Next, the patient can allow an active probiotic yogurt to sit on the tongue for at least 1 minute to repopulate it with healthy oral bacteria.

If symptoms persist, prescribe gabapentin 100 to 300 mg to be taken at bedtime. Cevimeline 30 mg 3 times daily can be added to treat symptoms of xerostomia. As a last resort, a low daily dose of trifluoperazine 1 to 2 mg may alleviate the dysesthesia of OD. Because this medication is an antipsychotic, there is an increased risk for adverse effects such as tardive dyskinesia; however, given that we recommend using at most one-twentieth of the dose recommended for psychiatric illnesses such as schizophrenia, the risk appears to be minimal.⁵

We have found this protocol to be more structured, and in our practice, it has led to better outcomes than previously described therapeutic interventions.

Practice Implications

As a chronic condition, OD can be frustrating for patients, as many of them have attempted multiple treatments without success. It also may be challenging for dermatologists who are unfamiliar with its management. This approach to OD provides simple step-by-step diagnostic and therapeutic plans for a condition with an often-uncertain etiology and stubborn response to initial treatments. By following this protocol, dermatologists can be confident in their ability to help patients find relief from OD.

Practice Gap

Orodynia (OD)—together with glossodynia colloquially termed “burning mouth syndrome”—is a chronic disorder characterized by a burning sensation within the oral cavity without objective clinical signs. It is most common in perimenopausal and postmenopausal women.^1,2

Orodynia is a diagnosis of exclusion and is considered after 4 to 6 months of normal imaging and laboratory test results.^1,2 Its pathophysiology is poorly understood, as it can be intermittent or continuous, manifest with a variety of symptoms, and affect various entities of the oral cavity.^3,4 The most common structure affected is the tongue, and symptoms may include xerostomia, dysgeusia, and discomfort.^1,2 Orodynia is a frustrating condition, as many patients do not respond to treatment and experience symptoms for years.^1-4

The current approach to management of OD typically involves a combination of psychosocial strategies and pharmacologic agents. The psychosocial component consists of coping mechanisms (eg, stress management techniques and behavioral therapies) aimed at alleviating the psychological impact of the condition. Pharmacologic agents such as antidepressants, anticonvulsants, and topical medications often are prescribed to address neuropathic pain and dry mouth symptoms.^1,2 Additionally, oral rinses, saliva substitutes, and dietary supplements may be recommended to counteract the discomfort associated with xerostomia.^1,2 However, there is no stepwise protocol, leaving these treatments to be trialed in a disorganized manner.²

The Tools

In our unique approach to managing OD, physicians may employ a variety of tools, including autoantibody profiles, noninvasive salivary gland analysis, saliva analysis, patch testing for allergens, and—if deemed necessary—a minor salivary gland biopsy. The use of specific prescription medications is included in the later stages of our approach.

The Technique

First, exclude inflammatory conditions such as geographic tongue, oral lichen planus, autoimmune bullous disorders, and other treatable conditions such as dyspepsia and Sjögren syndrome using the tools described above. Noninvasive modalities should be exhausted first, and dermatologists/clinicians should exercise clinical judgement to determine whether all options should be trialed, including more invasive/costly ones.

If symptoms persist, clinicians may want to obtain a culture for oral candida. If results are positive, candida may be treated quickly with oral fluconazole. If that treatment fails and fissuring is present, advise the patient on treating the tongue; we recommend lightly brushing the tongue once daily with a hydrogen peroxide 3% solution, followed by rinsing. Next, the patient can allow an active probiotic yogurt to sit on the tongue for at least 1 minute to repopulate it with healthy oral bacteria.

If symptoms persist, prescribe gabapentin 100 to 300 mg to be taken at bedtime. Cevimeline 30 mg 3 times daily can be added to treat symptoms of xerostomia. As a last resort, a low daily dose of trifluoperazine 1 to 2 mg may alleviate the dysesthesia of OD. Because this medication is an antipsychotic, there is an increased risk for adverse effects such as tardive dyskinesia; however, given that we recommend using at most one-twentieth of the dose recommended for psychiatric illnesses such as schizophrenia, the risk appears to be minimal.⁵

We have found this protocol to be more structured, and in our practice, it has led to better outcomes than previously described therapeutic interventions.

Practice Implications

As a chronic condition, OD can be frustrating for patients, as many of them have attempted multiple treatments without success. It also may be challenging for dermatologists who are unfamiliar with its management. This approach to OD provides simple step-by-step diagnostic and therapeutic plans for a condition with an often-uncertain etiology and stubborn response to initial treatments. By following this protocol, dermatologists can be confident in their ability to help patients find relief from OD.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

The US Drug Enforcement Agency (DEA) is moving forward with plans to move marijuana from a Schedule I to a Schedule III controlled substance under the Controlled Substance Act (CSA), the US Department of Justice officials announced this week. 

First reported by the Associated Press and since confirmed by this news organization through a US Department of Justice spokesperson, the news made international headlines. Despite the media splash, the final rule is still months away.

How did we get here? What happens next? What impact might rescheduling have on clinicians, patients, researchers, and the medical cannabis industry? 

Why Reschedule? Why Now? 

The DEA’s decision is based on a 2023 determination from the US Food and Drug Administration (FDA) that marijuana has a legitimate medical use and should be moved to Schedule III. 

DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. 

Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use.

Congress has allowed states leeway for the distribution and use of medical marijuana, and current and previous presidential administrations have chosen not to aggressively pursue prosecution of state-allowed marijuana use, the Congressional Research Service (CRS) reports. 

Pressure to address the conflict between federal and state laws and an increasing interest in drug development of cannabis and cannabis-derived products probably contributed to the DEA’s decision, said Stephen Strakowski, MD, professor, and vice chair of psychiatry at Indiana University in Indianapolis, and professor and associate vice president at University of Texas in Austin.

“The trend toward legalization is everywhere and even though nationally the feds in this instance are lagging the states, the pressure to legalize has been intense for 50 years and it’s not surprising that the DEA is finally following that lead,” Dr. Strakowski told this news organization. 

How Does Rescheduling Work? What’s the Timeline?

The DEA will submit a formal rule proposing that marijuana be moved from Schedule I to Schedule III to the White House Office of Management and Budget. The timing of the submission is unclear. 

Once the proposed rule is posted to the Federal Register, there will be a public comment period, which usually lasts 30-60 days.

“This will likely generate a lot of public comment,” Robert Mikos, JD, LaRoche Family Chair in Law at Vanderbilt University Law School in Nashville, Tennessee, told this news organization. “Then the agency has to go back and wade through those comments and decide if they want to proceed with the rule as proposed or modify it.”

A final rule will probably be posted before the end of the current presidential term in January, Mr. Mikos said. While a lawsuit blocking its implementation is possible, there is a “low chance that a court would block this,” he added.

How Will Rescheduling Affect Medical Marijuana?

For medical marijuana, changing the drug to a Schedule III means that it can legally be prescribed but only in states that have legalized medical cannabis, Mr. Mikos said. 

“If you’re a patient in a state with a medical marijuana law and your physician gives you a prescription for medical marijuana and you possess it, you will no longer be guilty of a federal crime,” he said.

Rescheduling could also benefit patients who receive care through the Veterans Administration (VA), Mr. Mikos said. For several years, the VA has had a policy that blocked clinicians from prescribing medical marijuana because as a Schedule I drug, it was determined to have no accepted medical use. 

“It’s possible the VA may drop that policy once the drug gets rescheduled. If you’re in a medical marijuana state, if you’re a VA patient, and you don’t want to spend the extra money to go outside that system, this will have meaningful impact on their lives,” Mr. Mikos said.

But what about patients living in states that have not legalized medical cannabis? 

“You still wouldn’t be committing a federal crime, but you could be violating state law,” Mr. Mikos said. “That’s a much more salient consideration because if you look at who goes after individuals who possess small amounts of drugs, the state handles 99% of those cases.” 

The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law.

What Does It Mean for Medical Marijuana Dispensaries?

Though rescheduling makes it legal for clinicians to prescribe medical marijuana and for patients to use it, the actual sale of the drug will remain illegal under federal law because rescheduling only changes prescribing under the CSA, Mr. Mikos said.

“If you’re a dispensary and you sell it, even if it’s to somebody who’s got a prescription, you’re still probably violating the Food, Drug and Cosmetics Act. Rescheduling doesn’t change that,” he said. 

“Even assuming the DEA follows through with this and it doesn’t come undone at some future date, the industry is still going struggle to comply with the Controlled Substances Act post rescheduling because that statute is going to continue to impose a number of regulations on the industry,” Mr. Mikos added.

However, rescheduling would change the tax status of the estimated 12,000-15,000 state-licensed cannabis dispensaries in the United States, allowing access to certain tax deductions that are unavailable to sales involving Schedule I controlled substances, James Daily, JD, MS, with Center for Empirical Research in the Law at Washington University School of Law in St. Louis, told this news organization.

“Many cannabis businesses do in fact pay federal taxes, but the inability to take any federal tax credits or deductions means that their effective tax rate is much higher than it would otherwise be,” Mr. Daily said. 

Although new federal tax deductions would likely available to cannabis businesses if marijuana were rescheduled to Schedule III, “their business would still be in violation of federal law,” he said. 

“This creates a further tension between state and federal law, which could be resolved by further legalization or it could be resolved by extending the prohibition on tax deductions to include cannabis and not just Schedule I and II drugs,” he added.

Will Rescheduling Make It Easier to Conduct Cannabis-Related Research? 

Research on medical cannabis has been stymied by FDA and DEA regulations regarding the study of Schedule I controlled substances. Although rescheduling could lift that barrier, other challenges would remain.

“Schedule III drugs can be more easily researched, but it’s unclear if, for example, a clinical trial could lawfully obtain the cannabis from a dispensary or if they would still have to go through the one legal federal supplier of cannabis,” Daily said. 

The FDA reports having received more than 800 investigational new drug applications for and pre-investigational new drug applications related to cannabis and cannabis-derived products since the 1970s, the agency reports. To date, the FDA has not approved any marketing drug applications for cannabis for the treatment of any disease or condition. 

In January 2023, the agency published updated guidelines for researchers and sponsors interested in developing drugs containing cannabis or cannabis-derived compounds. 

It’s unclear whether those guidelines would be updated if the rescheduling moves forward. 

Does Rescheduling Marijuana Pose Any Risk? 

In its report to the DEA that marijuana be rescheduled, the FDA was careful to note that the agency’s recommendation is “not meant to imply that safety and effectiveness have been established for marijuana that would support FDA approval of a marijuana drug product for a particular indication.”

That’s a notation that clinicians and patients should take to heart, Dr. Strakowski said. 

“It’s important to remind people that Schedule III drugs, by definition, have addiction and other side effect risks,” he said. “The celebrity marketing that sits behind a lot of this is incompletely informed. It’s portrayed as fun and harmless in almost every movie and conversation you see, and we know that’s not true.”

Previous studies have linked cannabis to increased risk for mania, anxiety disorders, and schizophrenia. 

“It is increasingly clear that marijuana use is linked to poor outcomes in people who struggle with mental illness,” Dr. Strakowski said. “We have no evidence that it can help you but there is evidence that it can harm you.”

Dr. Strakowski likens cannabis use to alcohol, which is a known depressant that is associated with worse outcomes in people with mental illness. 

“I think with cannabis, we don’t know enough about it yet, but we do know that it does have some anxiety risks,” he said. “The risks in people with mental illness are simply different than in people who don’t have mental illness.”

Dr. Strakowski, Mr. Mikos, and Mr. Daily report no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.

The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.

kali9/Getty Images

Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.

The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).

A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).

For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).

The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.

Physical Activity Types, Other Analyses

The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.

Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.

Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.

While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).

Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.

Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
 

Thigh Circumference as an Indicator of Muscle Mass

The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)

“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.

It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.

Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.

“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”

Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.

Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”

The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.

Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.

The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.

kali9/Getty Images

Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.

The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).

A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).

For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).

The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.

Physical Activity Types, Other Analyses

The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.

Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.

Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.

While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).

Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.

Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
 

Thigh Circumference as an Indicator of Muscle Mass

The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)

“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.

It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.

Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.

“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”

Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.

Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”

The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.

Weight-bearing recreational activity was associated with a 22% increased odds of developing knee osteoarthritis (OA) in a large prospective cohort study in the Netherlands, but notably, the increased risk was seen only in those with low levels of lower-limb muscle mass.

The findings point toward the value of “tailored advice” for physical activity, and suggest that “caution is needed when engaging in weight-bearing activity, especially for individuals with low levels of lower-limb muscle mass,” Yahong Wu, MD, and coinvestigators, of the Erasmus Medical Center in Rotterdam, the Netherlands, wrote in JAMA Network Open.

kali9/Getty Images

Investigators used data from sequential cohorts of the longitudinal Rotterdam Study, which enrolled people aged 45 and older starting in 1990. The 5003 participants in this new analysis of physical activity and knee OA had complete records of baseline recreational physical activity, baseline knee pain, and knee radiographs from both baseline and at least one follow-up exam. Those with radiographically defined knee OA at baseline were excluded.

The incident rate of radiographically defined (x-ray) knee OA among all participants was 8.4%, with a mean follow-up time of 6.33 years. Among 3492 individuals without baseline knee pain, the researchers found no increased odds of incident radiographic OA with non–weight-bearing activity (odds ratio [OR], 1.04; 95% CI, 0.95-1.15; P = .37) but a significant association of weight-bearing activity with OA incidence (OR, 1.22; 95% CI, 1.10-1.35; P < .001).

A stratification analysis of a subset of participants whose lower-limb mass had been measured by dual-energy x-ray absorptiometry (DXA) showed, however, that the association of weight-bearing activity with incident OA was limited to patients in the lowest third of lower-limb muscle mass index (LMI), who had a 53% increased likelihood of developing knee OA (OR, 1.53; 95% CI, 1.15-2.04; P = .003).

For patients in the middle and upper tertiles, there was no significant association between weight-bearing activity and the odds of incident OA (OR, 0.93; P = .73, and OR, 1.15; P = .40, respectively).

The findings are reassuring overall, said Kelli D. Allen, PhD, research professor of medicine and exercise physiologist at the University of North Carolina at Chapel Hill, who was asked to comment on the study. “The study corroborates prior research showing that for most people, weight-bearing recreational activity does not increase the risk of knee osteoarthritis. This should be encouraging for people who want to increase their physical activity,” she said.

Physical Activity Types, Other Analyses

The researchers assessed total, weight-bearing, and non–weight-bearing physical activity using two validated questionnaires (an adapted version of the Zutphen Physical Activity Questionnaire and the Longitudinal Aging Study Amsterdam physical activity questionnaire) that asked participants about the frequency and duration of various types of physical activity. Activity was quantified as metabolic equivalent of task (MET) hours per week, and weight-bearing activities were defined as those in which the knee joint bears the body’s weight.

Walking, gardening, golf, dancing, and ball sports were among the activities qualifying as weight-bearing activities. Non–weight-bearing activities included cycling, rowing, and swimming.

Sex, body mass index, and follow-up time were among the covariates adjusted for in the primary analysis. Similar results were found when adjustments were also made for educational level, alcohol intake, lipid levels, and diabetes.

While incident radiographic knee OA (measured using the Kellgren & Lawrence grading system) was the primary outcome, the researchers also looked at symptomatic knee OA, as defined by x-ray and a knee pain questionnaire, and found no significant association of its incidence with any of the exercise categories (total, weight-bearing, or non-weight-bearing).

Coauthor Joyce B. J. van Meurs, PhD, of the departments of internal medicine and orthopedics & sports medicine at Erasmus Medical Center, told this news organization that “pain as a subjective, recurrent symptom is more difficult to study … [and] a larger sample size or more precise measurements [of pain] in future studies would help to better understand the true association” of symptomatic knee OA and physical activity.

Similarly, analyses of the 1511 patients (out of 5003) who had knee pain at baseline found no significant association of weight-bearing or non–weight-bearing physical activity with incident radiographic knee OA. The trends were similar to those found in the population without knee pain, however, which suggests the analysis was underpowered, the researchers wrote, noting too that patients with baseline pain had lower activity levels than those without pain. (Low case numbers precluded a stratification analysis on LMI for incident symptomatic OA.)
 

Thigh Circumference as an Indicator of Muscle Mass

The findings build upon an international meta-analysis published in 2021 that found no association between total physical activity and knee OA and align with other studies suggesting a link between greater mechanical stress/strain and greater OA risk, the researchers wrote. (The meta-analysis couldn’t investigate different types of activity.)

“Although we cannot establish a causal relationship … we hypothesize that the mechanical loading on joints and cartilage could explain the association of weight-bearing activity with osteoarthritis in the low LMI tertile group,” they said.

It is possible that thigh muscle-specific strength or mass may temper the risk of knee OA, they wrote, but the lack of thigh strength data in the Rotterdam Study precluded such evaluation. Still, in everyday practice, the researchers noted, lower limb muscle function could be assessed using thigh circumference.

Dr. Allen agreed. “ ‘Gold standard’ assessment of muscle mass is not common in routine practice, but clinicians can evaluate muscle mass in other ways, such as thigh circumference,” she told this news organization, noting that measurement should align with procedures described by the National Health and Nutrition Examination Survey in its anthropometry procedures manual.

“If low lower-limb muscle mass is suspected, a referral to a physical therapist can be helpful for more formally assessing muscle mass and muscle strength,” she added, “and for instructions for a safe and appropriate exercise program for building muscle and protecting joints.”

Among other limitations of the study, according to the researchers, are an ethnically nondiverse population, the unavailability of knee injury data, and the assessment of physical activity only at baseline.

Moving forward, Dr. van Meurs told this news organization, “the main question regarding physical activity and OA is still, if people already have pain or early OA complaints, what kinds of sports they can do without hurting their joints?” This “should be tested,” she said, “in a real-life, ideally trial-like intervention study.”

The study was funded by the Erasmus Medical Center and Erasmus University as well as through various government grants. Dr. Wu also had study support from the China Scholarship Council. Two of the authors reported relationships with arthritis-related organizations. Dr. Allen reported having no disclosures relevant to her comments.

TOPLINE:

Differences in prodromal or early symptoms of mpox between White non-Hispanic patients and patients of color suggest healthcare disparities in vulnerable populations.

METHODOLOGY:

• There is limited information on the populations disproportionately affected by the recent global mpox outbreak, particularly in individuals with HIV and racial and ethnic minorities.
• To investigate morphologic and clinical presentations of mpox in diverse populations, researchers conducted a review of the records of 54 individuals (mean age, 42.4 years) diagnosed with mpox at a San Francisco clinic for patients with HIV or at high risk for HIV, between June and October 2022.
• All patients were assigned male at birth, and three identified themselves as transgender women.
• Morphologic descriptions were documented through either photographic evidence or physical examination notes.

TAKEAWAY:

• Pustules or pseudopustules were the most common morphologic finding in 57.1% of the White non-Hispanic patients and 62.5% of the patients of color (P = .72).
• White non-Hispanic patients were more likely to have no prodromal symptoms (50.0% vs 17.5%; P = .02) and were more likely to have genital lesions (78.6% vs 40.0%; P = .01) than patients of color. These differences were significant or nearly significant when White non-Hispanic patients were compared with Hispanic patients but not in other ethnic or racial groups.
• There were no differences in HIV viral loads or CD4 counts between racial and ethnic groups, and no variations in clinical presentations were observed based on CD4 counts.
• Patients with higher HIV viral loads were more likely to have concurrent sexually transmitted infections (57.1% vs 25%; P = .03).
• Symptoms resolved in all patients, regardless of medical intervention, within weeks of initial presentation, and there were no hospitalizations or deaths.

IN PRACTICE:

Considering that HIV viral burden was not significantly different between White non-Hispanic patients and patients of color, the difference in presentation of the prodrome “may indicate disparities in vulnerable populations,” the authors wrote, noting that more research in large groups is needed to confirm their results.

SOURCE:

The study, led by Richard W. Kim, BS, from the University of California San Francisco, was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Inclusion of “other” racial category in the records highlighted potential inaccuracies in data representation.

DISCLOSURES:

The study received no external funding. The authors did not declare any competing interests.

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

TOPLINE:

Differences in prodromal or early symptoms of mpox between White non-Hispanic patients and patients of color suggest healthcare disparities in vulnerable populations.

METHODOLOGY:

• There is limited information on the populations disproportionately affected by the recent global mpox outbreak, particularly in individuals with HIV and racial and ethnic minorities.
• To investigate morphologic and clinical presentations of mpox in diverse populations, researchers conducted a review of the records of 54 individuals (mean age, 42.4 years) diagnosed with mpox at a San Francisco clinic for patients with HIV or at high risk for HIV, between June and October 2022.
• All patients were assigned male at birth, and three identified themselves as transgender women.
• Morphologic descriptions were documented through either photographic evidence or physical examination notes.

TAKEAWAY:

• Pustules or pseudopustules were the most common morphologic finding in 57.1% of the White non-Hispanic patients and 62.5% of the patients of color (P = .72).
• White non-Hispanic patients were more likely to have no prodromal symptoms (50.0% vs 17.5%; P = .02) and were more likely to have genital lesions (78.6% vs 40.0%; P = .01) than patients of color. These differences were significant or nearly significant when White non-Hispanic patients were compared with Hispanic patients but not in other ethnic or racial groups.
• There were no differences in HIV viral loads or CD4 counts between racial and ethnic groups, and no variations in clinical presentations were observed based on CD4 counts.
• Patients with higher HIV viral loads were more likely to have concurrent sexually transmitted infections (57.1% vs 25%; P = .03).
• Symptoms resolved in all patients, regardless of medical intervention, within weeks of initial presentation, and there were no hospitalizations or deaths.

IN PRACTICE:

Considering that HIV viral burden was not significantly different between White non-Hispanic patients and patients of color, the difference in presentation of the prodrome “may indicate disparities in vulnerable populations,” the authors wrote, noting that more research in large groups is needed to confirm their results.

SOURCE:

The study, led by Richard W. Kim, BS, from the University of California San Francisco, was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Inclusion of “other” racial category in the records highlighted potential inaccuracies in data representation.

DISCLOSURES:

The study received no external funding. The authors did not declare any competing interests.

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

TOPLINE:

Differences in prodromal or early symptoms of mpox between White non-Hispanic patients and patients of color suggest healthcare disparities in vulnerable populations.

METHODOLOGY:

• There is limited information on the populations disproportionately affected by the recent global mpox outbreak, particularly in individuals with HIV and racial and ethnic minorities.
• To investigate morphologic and clinical presentations of mpox in diverse populations, researchers conducted a review of the records of 54 individuals (mean age, 42.4 years) diagnosed with mpox at a San Francisco clinic for patients with HIV or at high risk for HIV, between June and October 2022.
• All patients were assigned male at birth, and three identified themselves as transgender women.
• Morphologic descriptions were documented through either photographic evidence or physical examination notes.

TAKEAWAY:

• Pustules or pseudopustules were the most common morphologic finding in 57.1% of the White non-Hispanic patients and 62.5% of the patients of color (P = .72).
• White non-Hispanic patients were more likely to have no prodromal symptoms (50.0% vs 17.5%; P = .02) and were more likely to have genital lesions (78.6% vs 40.0%; P = .01) than patients of color. These differences were significant or nearly significant when White non-Hispanic patients were compared with Hispanic patients but not in other ethnic or racial groups.
• There were no differences in HIV viral loads or CD4 counts between racial and ethnic groups, and no variations in clinical presentations were observed based on CD4 counts.
• Patients with higher HIV viral loads were more likely to have concurrent sexually transmitted infections (57.1% vs 25%; P = .03).
• Symptoms resolved in all patients, regardless of medical intervention, within weeks of initial presentation, and there were no hospitalizations or deaths.

IN PRACTICE:

Considering that HIV viral burden was not significantly different between White non-Hispanic patients and patients of color, the difference in presentation of the prodrome “may indicate disparities in vulnerable populations,” the authors wrote, noting that more research in large groups is needed to confirm their results.

SOURCE:

The study, led by Richard W. Kim, BS, from the University of California San Francisco, was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Inclusion of “other” racial category in the records highlighted potential inaccuracies in data representation.

DISCLOSURES:

The study received no external funding. The authors did not declare any competing interests.

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

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

DENVER — Among patients with major depressive disorder, transcranial magnetic stimulation (TMS) had similar efficacy to electroconvulsive therapy (ECT), according to results from a retrospective study of patients treated in the past 20 years.

“We always learn in our textbooks that after about two or three medication trials is when you can start exploring more serious treatment protocols, such as ECT or TMS, but a lot of these patients weren’t going forward with it, and I was curious about it. I figured that TMS, which is a less expensive, less scary procedure that patients would more likely be open to, that is also approved for treatment resistant depression, would be a good alternative to ECT,” said Anuttham Kandhadai, a third-year medical student at University of Texas Medical Branch at Galveston, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
 

Study Findings Lead to More Questions

The researchers found lower rates of depressive episodes, suicidal attempts, and suicidal ideation among patients treated with TMS, but an important limitation was that the researchers did not know the severity of the depression in the two patient groups, according to Branch Coslett, MD, who attended the session and has performed research with TMS to treat aphasia in stroke patients. “I think it’s a very interesting study, and certainly something worth pursuing, but given that ECT is only used as a last resort, whereas TMS is often used as a second-line therapy, I think you’re really talking about very different populations that have had these treatments,” said Dr. Coslett.

Mr. Kandhadai recognized the limitations of the study and looks forward to expanding the research. “I’d love to explore cost effectiveness of the treatments. I’d love to explore patient familiarity and patient comfort with different treatments. And I’d also love to explore a more controlled study that can determine how severe someone’s depression is, and then be able to control for that and explore the outcomes based on the treatment protocol,” he said.

The ideal comparative study would be prospective, “but that will never be done. One Flew Over the Cuckoo’s Nest and similar sources of information have really poisoned the well,” said Dr. Coslett. However, he noted that advances have been made in ECT, and that targeting the right hemisphere produces fewer side effects: “The outcomes from unilateral right hemisphere stimulation are said to be every bit as good or maybe better, and you don’t get the confusion, you don’t get the memory loss, you don’t get all that sort of stuff that you’d expect when somebody has a prolonged, generalized tonic-clonic seizure.”

Still, people are naturally reluctant to undergo ECT. “I’ve seen it. It’s pretty barbaric. It’s better now and at my institution, people do get it, but they really, really have to be intractable,” he said.
 

Comparing Treatment Options

Mr. Kandhadai and his co-authors used the TriNetX database to identify patients with treatment-resistant major depressive disorder who received TMS or ECT in the past 20 years. There were 2,916 patients in both cohorts, who were matched by age, sex, ethnicity, mood and behavioral disorders, endocrine disorders, intellectual disabilities, cerebrovascular disease, and other nervous system disorders. The mean age at treatment was 48.2 years, 38.5% were male, and 3.1% were Black or African American.

Short-term outcomes favored TMS, including the frequency of disorientation (0.41% vs 2.81%), retrograde amnesia (0.34% vs 0.65%), and headache (4.36% vs 7.20%). Long-term outcomes from 1 month to 5 years post treatment were also better in the TMS group, including depressive episodes (44.99% vs 53.77%), suicide attempts (3.98% vs 6.86%), and suicidal ideation (12.38% vs 23.49%). Kaplan-Meier curve analysis between 1 month and 5 years showed a benefit to TMS in probability of not experiencing a depressive episode, and not experiencing suicidal ideation.

“ECT has been the gold standard of treatment resistant depression for a long time, and it deserves to be. I think it’s something you should offer your patients. Not everyone might be comfortable with it, and if they’re not, I think it’s important to not stop the conversation there, but to offer something like TMS because TMS is something that might be more accessible to patients. It might be more affordable, and it might be less scary,” said Mr. Kandhadai

Mr. Kandhadai and Dr. Coslett have no relevant financial disclosures.

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Most people experiencing homelessness have mental health disorders, according to a systematic review and meta-analysis.

In an examination of studies that included nearly 50,000 participants, the current prevalence of mental health disorders among people experiencing homelessness was 67% and the lifetime prevalence was 77%.

“The relationship is likely bidirectional, where experiencing homelessness may exacerbate mental health symptoms or where having a mental health disorder may increase an individual’s risk for experiencing homelessness,” lead author Rebecca Barry, PhD, a postdoctoral fellow at the University of Calgary in Calgary, Alberta, Canada, told this news organization. 

“There are also likely stressors that increase both risk for homelessness and risk for developing mental health disorders. This study examines prevalence but does not examine causal relationships,” she said.

The findings were published in JAMA Psychiatry.
 

A Growing Problem 

To determine the current and lifetime prevalence of mental health disorders among the homeless population, the researchers analyzed 85 studies that examined this question in participants aged ≥ 18 years. The review included 48,414 participants, including 11,154 (23%) women and 37,260 (77%) men.

The lifetime prevalence of mental health disorders was significantly higher in men experiencing homelessness (86%) than in women (69%). The most common mental health disorder was substance use disorder (44%), followed by antisocial personality disorder (26%), major depression (19%), bipolar disorder (8%), and schizophrenia (7%).

The prevalence of current and lifetime mental health disorders among the homeless population was higher than that that observed in the general population (13%-15% and 12%-47%, respectively).

The results resembled those of a previous review that estimated that 76% of people experiencing homelessness living in high-income countries have mental health disorders.

“Even though our results are not surprising, they still are drawing attention to this issue because it is a big problem in Canada, the United States, Europe, and other places,” senior author Dallas Seitz, MD, PhD, professor of psychiatry at the University of Calgary’s Cumming School of Medicine, told this news organization. “The problem is concerning, and it’s not getting better. Addiction and mental health problems are becoming more common among people who are homeless.” 

The bottom line is that people need affordable housing and mental health support, said Dr. Seitz. “It’s a housing problem and a health problem, and we need adequate resources to find better ways for those two systems to collaborate. There are public safety concerns, and we have to try and bring services to people experiencing homelessness. You have to come and meet people where they’re at. You have to try and establish a trusting relationship so that we can get people on the path to recovery.”
 

‘It’s Really About Income’ 

Commenting on the findings for this news organization, Stephen Hwang, MD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said, “There have been previous studies of this type, but it is good to have an updated one.” Dr. Hwang, who is also chair in Homelessness, Housing, and Health at St. Michael’s Hospital, did not participate in the research. 

The findings must be understood in the proper context, he added. For one thing, grouping together all mental health disorders and giving a single prevalence figure can be misleading. “They are including in that category a diverse group of conditions. Substance use disorder, personality disorder, schizophrenia, and depression are all lumped together. The 67% prevalence seems very high, but it is a combination of many different conditions. I just don’t want people to look at that number and think that this means that everyone is a substance user or everyone has schizophrenia,” said Dr. Hwang. 

Also, some readers might interpret the findings to mean that mental problems are the reason people are homeless, he added. “That would be an incorrect interpretation because what this study is showing is that people with mental health disorders have a higher risk for becoming homeless. It doesn’t mean that it caused their homelessness. What really causes homelessness is a lack of affordable housing,” said Dr. Hwang.

“In a city or community where housing is very expensive, there’s not enough for everyone to be housed, there is a lot of competition for housing, and there’s not enough affordable housing for a number of reasons, we know that people with mental health conditions and substance use disorders will be among the first to lose their housing,” he said.

“It’s really about income. There are many reasons why a person cannot afford housing. So, not being able to earn enough money to afford it because you have a mental health disorder or substance use disorder is a common underlying reason for homelessness.”

Dr. Hwang also pointed out that people with mental illness who can access support, either through family members or through mental health care, and who also have the income to afford such services do not become homeless.

“Schizophrenia is seen in every population of the world at a rate of 1%. But you travel to certain cities and you see people who appear to have schizophrenia wandering the streets, and you go to other cities in the world and you don’t see anyone who looks like they’re homeless and have schizophrenia,” he said. 

“It’s not because there are fewer people with schizophrenia in those cities or countries; it’s because people with schizophrenia are treated differently. The rate of homelessness is determined not by how many people have that condition [eg, schizophrenia] but by how we treat those people and how we set up our society to either support or not support people who have disabilities.”

The study was funded by the Precision Care With Information, Science and Experience – Mental Health grant funded by the Calgary Health Foundation. Dr. Barry is supported by the Harley Hotchkiss Samuel Weiss Postdoctoral Fellowship awarded by the Hotchkiss Brain Institute at the University of Calgary. Dr. Barry reported having no relevant financial relationships. Dr. Seitz reported grants from Calgary Health Foundation during the conduct of the study as well as grants from University Health Foundation, the Canadian Institutes of Health Research, the Public Health Agency of Canada, the Alzheimer’s Association, and the Hotchkiss Brain Institute. He received honoraria for guideline development from the Canadian Coalition for Seniors Mental Health outside the submitted work. Dr. Hwang reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.

Amyloidosis is a condition marked by the accumulation of insoluble beta-sheet fibrillar protein aggregates in tissues that can be acquired or hereditary. Hereditary amyloidogenic transthyretin (hATTR) amyloidosis is an autosomal-dominant disease caused by pathogenic variants in the TTR gene. The TTR protein is essential for transporting thyroxine and retinol-binding protein and is primarily synthesized in the liver, becoming unstable as a result of the pathogenic mutations. Inherited pathogenic variants lead to the protein’s misfolding, aggregation, and deposition as amyloid fibrils in different organs, resulting in progressive multisystem dysfunction. hATTR amyloidosis is a heterogenous disease, characterized by a wide range of clinical manifestations affecting the peripheral (both somatic and autonomic) nervous system, heart, kidneys, and central nervous system (CNS); however, the heart and peripheral nerves appear to be the main targets of the TTR-related pathologic process. Without treatment, the prognosis is poor, with an average life expectancy of 7-11 years; however, in recent years, the development of new therapeutics has brought new hope to patients.

Here are five things to know about hereditary amyloidosis.
 

1. Diagnosis of hereditary amyloidosis requires a high level of suspicion.

The diagnosis of hATTR amyloidosis presents a significant challenge, particularly in nonendemic regions where a lack of family history and heterogeneity of clinical presentation can delay diagnosis by 4-5 years. A timely diagnosis requires clinicians to maintain a high index of suspicion, especially when evaluating patients with neuropathic symptoms. Early diagnosis is crucial to begin patients on recently available disease-modifying therapies that can slow the disease course. Failure to recognize is the major barrier to improved patient outcomes.

Confirming the diagnosis involves detecting amyloid deposits in tissue biopsy specimens from various possible sites, including the skin, nerves, myocardium, and others. However, the diagnosis can be challenging owing to the uneven distribution of amyloid fibrils, sometimes requiring multiple biopsies or alternative diagnostic approaches, such as TTR gene sequencing, to confirm the presence of an amyloidogenic pathogenic variant. Biopsy for hATTR amyloidosis is not required if imaging of the clinical phenotype and genetic testing are consistent.

Once diagnosed, the assessment of organ involvement is essential, using nerve conduction studies, cardiac investigations (eg, echocardiography, ECG, scintigraphy), ophthalmologic assessments, and complete renal function evaluations to fully understand the extent of disease impact.
 

2. Hereditary amyloidosis diseases are classified into two primary categories.

Hereditary amyloidosis represents a group of diseases caused by inherited gene mutations and is classified into two main types: ATTR (transthyretin-related) and non-TTR. Most cases of hereditary amyloidosis are associated with the TTR gene. Mutations in this protein lead to different forms of ATTR amyloidosis, categorized on the basis of the specific mutation involved, such as hATTR50M (genotype Val50Met), which is the most prevalent form.

ATTR mutations result in a variety of health issues, manifesting in three primary forms:

• Neuropathic ATTR (genotype Val50Met): Early symptoms include sensorimotor polyneuropathy of the legs, carpal tunnel syndrome, autonomic dysfunction, constipation/diarrhea, and impotence; late symptoms include cardiomyopathy, vitreous opacities, glaucoma, nephropathy, and CNS symptoms.
• Cardiac ATTR (genotype Val142Ile): This type is characterized by cardiomegaly, conduction block, arrhythmia, anginal pain, congestive heart failure, and sudden death.
• Leptomeningeal ATTR (genotype Asp38Gly): This is characterized by transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages, dementia, ataxia, and psychosis.

Non-TTR amyloidoses are rarer than are ATTR variations and involve mutations in different genes that also have significant health impacts. These include proteins such as apolipoprotein AI, fibrinogen A alpha, lysozyme, apolipoprotein AII, gelsolin, and cystatin C. Each type contributes to a range of symptoms and requires individualized management approaches.
 

3. Heightened disease awareness has increased the recognized prevalence of hereditary amyloidosis.

hATTR amyloidosis has historically been recognized as a rare disease, with significant clusters in Portugal, Brazil, Sweden, and Japan and alongside smaller foci in regions such as Cyprus and Majorca. This disease›s variable incidence across Europe is now perceived to be on the rise. It is attributed to heightened disease awareness among healthcare providers and the broader availability of genetic testing, extending its recognized impact to at least 29 countries globally. The genetic landscape of hATTR amyloidosis is diverse, with over 140 mutations identified in the TTR gene. Among these, the Val50Met mutation is particularly notable for its association with large patient clusters in the endemic regions.

Morbidity and mortality associated with hATTR amyloidosis are significant, with an average lifespan of 7-11 years post diagnosis; however, survival rates can vary widely depending on the specific genetic variant and organ involvement. Early diagnosis can substantially improve outcomes; yet, for many, the prognosis remains poor, especially in cases dominated by cardiomyopathy. Genetics play a central role in the disease›s transmission, with autosomal-dominant inheritance patterns and high penetrance among carriers of pathogenic mutations. Research continues to uncover the broad spectrum of genetic variations contributing to hATTR amyloidosis, with ongoing studies poised to expand our understanding of its molecular underpinnings and potential treatment options.

4. The effect on quality of life is significant both in patients living with hATTR amyloidosis and their caregivers.

hATTR amyloidosis imposes a multifaceted burden on patients and their caregivers as the disease progresses. Symptoms range from sensorimotor impairment and gastrointestinal or autonomic dysfunction to heart failure, leading to significant health-related quality-of-life deficits. The systemic nature of hATTR amyloidosis significantly affects patients› lifestyles, daily activities, and general well-being, especially because it typically manifests in adulthood — a crucial time for occupational changes. The progression of hATTR amyloidosis exacerbates the challenges in maintaining employment and managing household chores, with symptomatic patients often unable to work and experiencing difficulties with absenteeism and presenteeism when they are able to work.

hATTR amyloidosis leads to physical, mental, occupational, and social limitations for patients, and it also places a considerable strain on their families and caregivers, who report poor mental health, work impairment, and a high time commitment (mean, 45.9 h/wk) to providing care.

5. There have been significant advancements in therapeutic options for early-stage hATTR amyloidosis.

After diagnosis, prompt initiation of treatment is recommended to delay the progression of hATTR amyloidosis; a multidisciplinary approach is essential, incorporating anti-amyloid therapy to inhibit further production and/or deposition of amyloid aggregates. Treatment strategies also include addressing symptomatic therapy and managing cardiac, renal, and ocular involvement. Although many therapies have been developed, especially for the early stages of hATTR amyloidosis, therapeutic benefits for patients with advanced disease remain limited.

Recent advancements in the treatment of hATTR amyloidosis have introduced RNA-targeted therapies including patisiran, vutrisiran, and eplontersen, which have shown efficacy in reducing hepatic TTR synthesis and the aggregation of misfolded monomers into amyloid deposits. These therapies, ranging from small interfering RNA formulations to antisense oligonucleotides, offer benefits in managing both cardiomyopathy and neuropathy associated with hATTR amyloidosis , administered through various methods, including intravenous infusions and subcutaneous injections. In addition, the stabilization of TTR tetramers with the use of drugs such as tafamidis and diflunisal has effectively prevented the formation of amyloidogenic monomers. Moreover, other investigational agents, including TTR stabilizers like acoramidis and tolcapone, as well as novel compounds that inhibit amyloid formation and disrupt fibrils, are expanding the therapeutic landscape for hATTR amyloidosis , providing hope for improved management of this complex condition.

Dr. Gertz is a professor and consultant in the Department of Hematology, Mayo Clinic, Rochester, Minnesota. He has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from AstraZeneca, Ionis, and Alnylym.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has designated the Eversense (Sensionics, Inc; Ascencia Diabetes Care) implanted continuous glucose monitor (CGM) an “integrated CGM,” meaning it can be used in conjunction with insulin pumps as part of an automated insulin delivery system (AID). 

The Eversense now joins Dexcom’s G6 and G7 and the Freestyle Libre 2 Plus in being compatible with multiple different branded insulin pumps as part of AID systems, and it is the only implantable one. 

The sensor device is inserted under the skin of the patient’s upper arm by a healthcare provider and a transmitter is worn over it on the skin. The FDA approved the Eversense in June 2018 for 3-month use and in February 2022  for use up to 6 months. It is indicated for people with diabetes aged 18 years and older.

Fingerstick blood glucose measurements are still required for calibration once a day after day 21, when symptoms don’t match the CGM information, or when taking tetracycline medications. 

According to Sensionics, the Eversense is “the most accurate CGM in the critical low glucose ranges with essentially no compression lows.” The latter refers to ‘false low’ alarms that sometimes occur when a person presses on the device, such as during sleep.

“As we look ahead, we are focused on progressing our partnership discussions and software developments, and look forward to providing more updates,” Sensionics said in a statement.
 

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

The US Food and Drug Administration (FDA) has designated the Eversense (Sensionics, Inc; Ascencia Diabetes Care) implanted continuous glucose monitor (CGM) an “integrated CGM,” meaning it can be used in conjunction with insulin pumps as part of an automated insulin delivery system (AID). 

The Eversense now joins Dexcom’s G6 and G7 and the Freestyle Libre 2 Plus in being compatible with multiple different branded insulin pumps as part of AID systems, and it is the only implantable one. 

The sensor device is inserted under the skin of the patient’s upper arm by a healthcare provider and a transmitter is worn over it on the skin. The FDA approved the Eversense in June 2018 for 3-month use and in February 2022  for use up to 6 months. It is indicated for people with diabetes aged 18 years and older.

Fingerstick blood glucose measurements are still required for calibration once a day after day 21, when symptoms don’t match the CGM information, or when taking tetracycline medications. 

According to Sensionics, the Eversense is “the most accurate CGM in the critical low glucose ranges with essentially no compression lows.” The latter refers to ‘false low’ alarms that sometimes occur when a person presses on the device, such as during sleep.

“As we look ahead, we are focused on progressing our partnership discussions and software developments, and look forward to providing more updates,” Sensionics said in a statement.
 

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

The US Food and Drug Administration (FDA) has designated the Eversense (Sensionics, Inc; Ascencia Diabetes Care) implanted continuous glucose monitor (CGM) an “integrated CGM,” meaning it can be used in conjunction with insulin pumps as part of an automated insulin delivery system (AID). 

The Eversense now joins Dexcom’s G6 and G7 and the Freestyle Libre 2 Plus in being compatible with multiple different branded insulin pumps as part of AID systems, and it is the only implantable one. 

The sensor device is inserted under the skin of the patient’s upper arm by a healthcare provider and a transmitter is worn over it on the skin. The FDA approved the Eversense in June 2018 for 3-month use and in February 2022  for use up to 6 months. It is indicated for people with diabetes aged 18 years and older.

Fingerstick blood glucose measurements are still required for calibration once a day after day 21, when symptoms don’t match the CGM information, or when taking tetracycline medications. 

According to Sensionics, the Eversense is “the most accurate CGM in the critical low glucose ranges with essentially no compression lows.” The latter refers to ‘false low’ alarms that sometimes occur when a person presses on the device, such as during sleep.

“As we look ahead, we are focused on progressing our partnership discussions and software developments, and look forward to providing more updates,” Sensionics said in a statement.
 

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

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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