Clinical Endocrinology News

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

ClaudioVentrella/Thinkstock

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

ClaudioVentrella/Thinkstock

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

ClaudioVentrella/Thinkstock

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Blogging is a great way to capture the attention of new patients and anyone interested in the diagnoses and procedures you specialize in. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.

Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.

Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.

By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)

The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.

You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.

That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.

Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.

Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.

Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.

If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics. 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

*This article was updated 10/17/2022.

Blogging is a great way to capture the attention of new patients and anyone interested in the diagnoses and procedures you specialize in. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.

Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.

Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.

By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)

The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.

You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.

That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.

Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.

Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.

Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.

If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics. 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

*This article was updated 10/17/2022.

Blogging is a great way to capture the attention of new patients and anyone interested in the diagnoses and procedures you specialize in. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.

Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.

Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.

By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)

The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.

You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.

That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.

Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.

Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.

Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.

If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics. 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

*This article was updated 10/17/2022.

The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.

The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.

One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.

Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.

Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.

SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.

Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.

References

SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644

SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341

Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false

The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.

The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.

One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.

Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.

Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.

SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.

Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.

References

SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644

SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341

Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false

The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.

The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.

One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.

Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.

Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.

SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.

Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.

References

SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644

SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341

Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false

In November 2021, the National Organization for Rare Disorders (NORD) announced that it had designated 31 institutions across the United States as “NORD Rare Disease Centers of Excellence.” More than just a stamp of approval, the new NORD network aims to change the way rare diseases are diagnosed and treated, creating more efficient pathways for collaboration among physicians, while helping patients get better care closer to home.

To understand better how the nascent network can benefit patients and clinicians, Neurology Reviews/MDedge Neurology spoke with Ed Neilan, MD, PhD, NORD’s chief scientific and medical officer. Dr. Neilan, a pediatrician and geneticist, is a former president of the medical staff at Boston Children’s Hospital and also served as head of global medical affairs for rare neurology at Sanofi Genzyme.

How did NORD choose its 31 centers?

We were looking for places that had both broad capabilities and deep expertise, where it was reasonable to expect that a patient with almost any condition could go and, without too many missteps or delays, get the right diagnosis or the right treatment. We also sought sites that were educating the next generation of rare disease specialists across departments. The sites had to be involved in research, because that moves the field forward, and sometimes it’s the only way to get a really impactful treatment for the 95% of rare diseases that don’t have an FDA-approved treatment. NORD sent a letter inviting different centers to apply, along with an application that had 120 questions. Most of the questions sought information about what kinds of expertise or services were available on-site, so that patients don’t have to go elsewhere to get, let’s say, a brain MRI scan or to see an immunologist. We wanted each site to be a place where you could go for almost any problem, at any age, and expect that while you’re being seen, and receiving treatment, it can also contribute to the education of the next generation of rare disease specialists and to research.

Several of the members of the network comprise more than one institution: They’re a children’s hospital combined with another facility.

Children’s hospitals, which are highly specialized and able to care for rare things in children, couldn’t apply by themselves. They had to apply in partnership with a center that could provide adult care as patients got older; otherwise, their care model would be incomplete. We’ve had some small victories already just by asking these questions and outlining this sort of approach. At one institution in the Great Plains, the director told us that he had been trying for years to get permission to hire someone who could make appointments across three different hospitals – a children’s hospital and two adult hospitals. He’d wanted to ensure that patients with rare and genetic diseases were seen in the appropriate places, and thanks to the NORD designation, he finally can. Now, regardless of age, the same office staff can handle the arrangements, and the patient will be scheduled in the right place.

You make clear that these are different from disease-specific centers of excellence – you specifically chose the 31 centers for their breadth of expertise. There’s no way to represent all 7,000 rare diseases equally, and disease-specific centers of excellence, which already exist for hemophilia, muscular dystrophy, cystic fibrosis, and some other conditions, have a very important role. We’re not aiming to compete with any other existing resources. What we are seeking to do is to fill the unmet need of, “What if there are no such designations for the disease that you’re concerned about?” Our goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.

The delay to diagnosis can be years in rare diseases. How can the network help speed up diagnoses?

With all these experts on different diseases, we hope to develop some better diagnostic algorithms within the network. Another thing we can do is to share resources. With 31 sites, everybody’s seeing patients with unknown diagnoses. Everyone is seeing patients for whom they would maybe like to get a whole genome done, or a whole exome done, but they are often encountering stiff resistance from insurance companies.

Meanwhile some sites, but not all 31, have multimillion-dollar grants to do sequencing and other kinds of advanced diagnostic tests to solve unknown cases. And there are people at those sites who say, “We need more samples. Can you get us samples from the other sites?”

One of the main things we aim to do is share information, including information about available diagnostic resources. We want all 31 sites to know which sites have funding and programs that enable them to study samples for other sites. We also want to know what criteria they’re putting on it. Someone might say: “I’ve got a grant to sequence genomes for people with unexplained seizures. Send me all your unexplained seizures.” Somebody else might have a grant for unexplained GI diseases. So, we want to put on our intranet a resource for the 31 sites, kind of a cookbook for – when if you can’t get it paid for by insurance, but you really think you need a particular special test – who might be able to do it for you within the network.

This would seem to benefit research across sites as well.

Yes, but we also want to share clinical advice and expertise for direct patient benefit. So, it doesn’t always have to fulfill the goals of a specific research project. For example, we might be able to create an undiagnosed patient quality improvement database across all 31 sites that could compliantly let Drs. X and Y know that they’re each seeing a patient with the same rare thing.

But let’s say you want to move the field forward by discovering a new disease. Rare genetic diseases are now being discovered at the rate of about 250 a year, so about 5 per week across the world. With two or three unrelated patients who have the same disease and a whole exome sequence, you can potentially discover a disease. Maybe you’ve found one unique patient with a genetic variant of possible significance, but you can’t be 100% sure, and you may not be able to convince your colleagues, or journal editors, until you find other cases. You need those two or three ultrarare patients. Within this network, a lot of sites want to share information about their ultrarare patients and be able to put together additional instances of the same thing, to prove that it is a real disease, to learn more about it and how to diagnose, manage, and treat it.

Part of the idea with a nationwide network is that patients aren’t going to have to move around among these centers of excellence, is that correct? They’re going to be seen at the closest ones, and it’s the expertise that is mobile.

Yes, that’s right. While we can’t eliminate the need for travel, what we are trying to do is increase the sharing of expertise, to improve results for patients while limiting the need for traveling very long distances. As a geneticist I’ve been on both the requesting and the receiving end of consultations with doctors at other sites, sometimes very far away, especially for ultrarare conditions for which any one physician’s experience is limited. We all try to honor these sorts of requests, but insurance doesn’t reimburse it and so hospitals don’t give doctors much credit for it.

We want to ultimately find ways to incentivize this type of collaboration. Hopefully we can get agreements with insurance companies to allow intersite consultations within our network, recognizing that they don’t want to pay for the patient to be seen out of state, but you also want the patient to get the best possible medical advice. This might require legislative changes in the long run. But what we can do more readily is create a culture within this network of mutual consultation and sharing of clinical experience. Outside of such a network, the idea of “cold calling” somebody, whom you may never have met, and asking them for help and free advice is a little bit of a bar, right? We want to lower that bar.

Can patients get telemedicine consults with physicians across the network?

NORD supports having telemedicine options for everybody regardless of diagnosis, rare or not, and we support legislation that would continue access and reimbursement for telemedicine post pandemic. I hope we can get that, or at least preserve telemedicine for rare diseases, for which there are often not enough, or sometimes not any, expert providers in the same state. Ultimately, we want patients to be able to get the expert assessments and advice they need. For rare diseases, that sometimes means battling back and forth with an insurance provider, seeking permission to see an expert clinician a thousand miles away. By sharing medical expertise, and through telemedicine when that’s allowed, we hope to reduce the need for that. But the telemedicine environment is still evolving and somewhat uncertain.

How will the network’s physician collaborations take place?

One of the important things NORD is providing to the network is an information technology setup and intranet across the 31 sites. That intranet is where center staff will go to access the network’s internal resources, including live and recorded case conferences. In those case conferences you can present a case you haven’t been able to solve. Experts you may have only heard of by reputation will now be streamed to your computer as part of the nationwide network. It benefits the patient because you get additional expert opinions, but it also benefits the physicians because we have this collegial space for discussion and learning. We’ll be linked by frequent meetings – some in person, most virtual – a common culture, and a common intranet.

On the intranet, we will also have a growing set of useful databases, links, and documents that are available to all members. These will be progressively updated with help from experts at the centers, so that clinicians can more directly learn from each other, instead of separately reinventing the wheel. The way things usually work, when you see a patient with an ultrarare condition that you’re not that familiar with, is that you tell them what little you can, then schedule them to come back in a few weeks. In the meantime, usually in your off time, you spend hours searching PubMed and other sources and you try to piece things together, to figure out what’s known that might help your patient. But imagine that this has already been figured out by someone else in the network. You can see on the network a list of articles the other expert read and found helpful in addressing this problem. And you then reach out directly to that other expert.

In recent months you’ve had one-on-one meetings with all 31 directors at the sites, and after that you convened 11 working groups. What are you trying to achieve?

Once the sites were chosen, we aimed to talk quickly and honestly about what everyone needed, what everyone saw as the biggest problems to tackle in rare diseases. Two things were very rewarding about those phone calls: one, all the centers were very enthusiastic, and two, they pretty much all agreed on what the key unmet needs are for rare disease patients and the practitioners trying to help them. So, we empaneled working groups of expert volunteers enthusiastic to work on each of those problems. These groups collectively comprise more than 200 volunteers – faculty, staff, and trainees – from the different sites nationwide. Each group is working on a key unmet need in rare diseases, and each group will be given its own space on our file-sharing platform, where they can share information and co-develop new ideas and documents. When something they produce is good enough to start to be a practice resource, such as a draft treatment guideline that the working group now wants to try in the real world, but it’s not yet ready to be published, they can share it and have it tested by all 31 sites through the dedicated intranet we are building for the network.

Jennie Smith is a freelance journalist specializing in medicine and health.

In November 2021, the National Organization for Rare Disorders (NORD) announced that it had designated 31 institutions across the United States as “NORD Rare Disease Centers of Excellence.” More than just a stamp of approval, the new NORD network aims to change the way rare diseases are diagnosed and treated, creating more efficient pathways for collaboration among physicians, while helping patients get better care closer to home.

To understand better how the nascent network can benefit patients and clinicians, Neurology Reviews/MDedge Neurology spoke with Ed Neilan, MD, PhD, NORD’s chief scientific and medical officer. Dr. Neilan, a pediatrician and geneticist, is a former president of the medical staff at Boston Children’s Hospital and also served as head of global medical affairs for rare neurology at Sanofi Genzyme.

How did NORD choose its 31 centers?

We were looking for places that had both broad capabilities and deep expertise, where it was reasonable to expect that a patient with almost any condition could go and, without too many missteps or delays, get the right diagnosis or the right treatment. We also sought sites that were educating the next generation of rare disease specialists across departments. The sites had to be involved in research, because that moves the field forward, and sometimes it’s the only way to get a really impactful treatment for the 95% of rare diseases that don’t have an FDA-approved treatment. NORD sent a letter inviting different centers to apply, along with an application that had 120 questions. Most of the questions sought information about what kinds of expertise or services were available on-site, so that patients don’t have to go elsewhere to get, let’s say, a brain MRI scan or to see an immunologist. We wanted each site to be a place where you could go for almost any problem, at any age, and expect that while you’re being seen, and receiving treatment, it can also contribute to the education of the next generation of rare disease specialists and to research.

Several of the members of the network comprise more than one institution: They’re a children’s hospital combined with another facility.

Children’s hospitals, which are highly specialized and able to care for rare things in children, couldn’t apply by themselves. They had to apply in partnership with a center that could provide adult care as patients got older; otherwise, their care model would be incomplete. We’ve had some small victories already just by asking these questions and outlining this sort of approach. At one institution in the Great Plains, the director told us that he had been trying for years to get permission to hire someone who could make appointments across three different hospitals – a children’s hospital and two adult hospitals. He’d wanted to ensure that patients with rare and genetic diseases were seen in the appropriate places, and thanks to the NORD designation, he finally can. Now, regardless of age, the same office staff can handle the arrangements, and the patient will be scheduled in the right place.

You make clear that these are different from disease-specific centers of excellence – you specifically chose the 31 centers for their breadth of expertise. There’s no way to represent all 7,000 rare diseases equally, and disease-specific centers of excellence, which already exist for hemophilia, muscular dystrophy, cystic fibrosis, and some other conditions, have a very important role. We’re not aiming to compete with any other existing resources. What we are seeking to do is to fill the unmet need of, “What if there are no such designations for the disease that you’re concerned about?” Our goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.

The delay to diagnosis can be years in rare diseases. How can the network help speed up diagnoses?

With all these experts on different diseases, we hope to develop some better diagnostic algorithms within the network. Another thing we can do is to share resources. With 31 sites, everybody’s seeing patients with unknown diagnoses. Everyone is seeing patients for whom they would maybe like to get a whole genome done, or a whole exome done, but they are often encountering stiff resistance from insurance companies.

Meanwhile some sites, but not all 31, have multimillion-dollar grants to do sequencing and other kinds of advanced diagnostic tests to solve unknown cases. And there are people at those sites who say, “We need more samples. Can you get us samples from the other sites?”

One of the main things we aim to do is share information, including information about available diagnostic resources. We want all 31 sites to know which sites have funding and programs that enable them to study samples for other sites. We also want to know what criteria they’re putting on it. Someone might say: “I’ve got a grant to sequence genomes for people with unexplained seizures. Send me all your unexplained seizures.” Somebody else might have a grant for unexplained GI diseases. So, we want to put on our intranet a resource for the 31 sites, kind of a cookbook for – when if you can’t get it paid for by insurance, but you really think you need a particular special test – who might be able to do it for you within the network.

This would seem to benefit research across sites as well.

Yes, but we also want to share clinical advice and expertise for direct patient benefit. So, it doesn’t always have to fulfill the goals of a specific research project. For example, we might be able to create an undiagnosed patient quality improvement database across all 31 sites that could compliantly let Drs. X and Y know that they’re each seeing a patient with the same rare thing.

But let’s say you want to move the field forward by discovering a new disease. Rare genetic diseases are now being discovered at the rate of about 250 a year, so about 5 per week across the world. With two or three unrelated patients who have the same disease and a whole exome sequence, you can potentially discover a disease. Maybe you’ve found one unique patient with a genetic variant of possible significance, but you can’t be 100% sure, and you may not be able to convince your colleagues, or journal editors, until you find other cases. You need those two or three ultrarare patients. Within this network, a lot of sites want to share information about their ultrarare patients and be able to put together additional instances of the same thing, to prove that it is a real disease, to learn more about it and how to diagnose, manage, and treat it.

Part of the idea with a nationwide network is that patients aren’t going to have to move around among these centers of excellence, is that correct? They’re going to be seen at the closest ones, and it’s the expertise that is mobile.

Yes, that’s right. While we can’t eliminate the need for travel, what we are trying to do is increase the sharing of expertise, to improve results for patients while limiting the need for traveling very long distances. As a geneticist I’ve been on both the requesting and the receiving end of consultations with doctors at other sites, sometimes very far away, especially for ultrarare conditions for which any one physician’s experience is limited. We all try to honor these sorts of requests, but insurance doesn’t reimburse it and so hospitals don’t give doctors much credit for it.

We want to ultimately find ways to incentivize this type of collaboration. Hopefully we can get agreements with insurance companies to allow intersite consultations within our network, recognizing that they don’t want to pay for the patient to be seen out of state, but you also want the patient to get the best possible medical advice. This might require legislative changes in the long run. But what we can do more readily is create a culture within this network of mutual consultation and sharing of clinical experience. Outside of such a network, the idea of “cold calling” somebody, whom you may never have met, and asking them for help and free advice is a little bit of a bar, right? We want to lower that bar.

Can patients get telemedicine consults with physicians across the network?

NORD supports having telemedicine options for everybody regardless of diagnosis, rare or not, and we support legislation that would continue access and reimbursement for telemedicine post pandemic. I hope we can get that, or at least preserve telemedicine for rare diseases, for which there are often not enough, or sometimes not any, expert providers in the same state. Ultimately, we want patients to be able to get the expert assessments and advice they need. For rare diseases, that sometimes means battling back and forth with an insurance provider, seeking permission to see an expert clinician a thousand miles away. By sharing medical expertise, and through telemedicine when that’s allowed, we hope to reduce the need for that. But the telemedicine environment is still evolving and somewhat uncertain.

How will the network’s physician collaborations take place?

One of the important things NORD is providing to the network is an information technology setup and intranet across the 31 sites. That intranet is where center staff will go to access the network’s internal resources, including live and recorded case conferences. In those case conferences you can present a case you haven’t been able to solve. Experts you may have only heard of by reputation will now be streamed to your computer as part of the nationwide network. It benefits the patient because you get additional expert opinions, but it also benefits the physicians because we have this collegial space for discussion and learning. We’ll be linked by frequent meetings – some in person, most virtual – a common culture, and a common intranet.

On the intranet, we will also have a growing set of useful databases, links, and documents that are available to all members. These will be progressively updated with help from experts at the centers, so that clinicians can more directly learn from each other, instead of separately reinventing the wheel. The way things usually work, when you see a patient with an ultrarare condition that you’re not that familiar with, is that you tell them what little you can, then schedule them to come back in a few weeks. In the meantime, usually in your off time, you spend hours searching PubMed and other sources and you try to piece things together, to figure out what’s known that might help your patient. But imagine that this has already been figured out by someone else in the network. You can see on the network a list of articles the other expert read and found helpful in addressing this problem. And you then reach out directly to that other expert.

In recent months you’ve had one-on-one meetings with all 31 directors at the sites, and after that you convened 11 working groups. What are you trying to achieve?

Once the sites were chosen, we aimed to talk quickly and honestly about what everyone needed, what everyone saw as the biggest problems to tackle in rare diseases. Two things were very rewarding about those phone calls: one, all the centers were very enthusiastic, and two, they pretty much all agreed on what the key unmet needs are for rare disease patients and the practitioners trying to help them. So, we empaneled working groups of expert volunteers enthusiastic to work on each of those problems. These groups collectively comprise more than 200 volunteers – faculty, staff, and trainees – from the different sites nationwide. Each group is working on a key unmet need in rare diseases, and each group will be given its own space on our file-sharing platform, where they can share information and co-develop new ideas and documents. When something they produce is good enough to start to be a practice resource, such as a draft treatment guideline that the working group now wants to try in the real world, but it’s not yet ready to be published, they can share it and have it tested by all 31 sites through the dedicated intranet we are building for the network.

Jennie Smith is a freelance journalist specializing in medicine and health.

In November 2021, the National Organization for Rare Disorders (NORD) announced that it had designated 31 institutions across the United States as “NORD Rare Disease Centers of Excellence.” More than just a stamp of approval, the new NORD network aims to change the way rare diseases are diagnosed and treated, creating more efficient pathways for collaboration among physicians, while helping patients get better care closer to home.

To understand better how the nascent network can benefit patients and clinicians, Neurology Reviews/MDedge Neurology spoke with Ed Neilan, MD, PhD, NORD’s chief scientific and medical officer. Dr. Neilan, a pediatrician and geneticist, is a former president of the medical staff at Boston Children’s Hospital and also served as head of global medical affairs for rare neurology at Sanofi Genzyme.

How did NORD choose its 31 centers?

We were looking for places that had both broad capabilities and deep expertise, where it was reasonable to expect that a patient with almost any condition could go and, without too many missteps or delays, get the right diagnosis or the right treatment. We also sought sites that were educating the next generation of rare disease specialists across departments. The sites had to be involved in research, because that moves the field forward, and sometimes it’s the only way to get a really impactful treatment for the 95% of rare diseases that don’t have an FDA-approved treatment. NORD sent a letter inviting different centers to apply, along with an application that had 120 questions. Most of the questions sought information about what kinds of expertise or services were available on-site, so that patients don’t have to go elsewhere to get, let’s say, a brain MRI scan or to see an immunologist. We wanted each site to be a place where you could go for almost any problem, at any age, and expect that while you’re being seen, and receiving treatment, it can also contribute to the education of the next generation of rare disease specialists and to research.

Several of the members of the network comprise more than one institution: They’re a children’s hospital combined with another facility.

Children’s hospitals, which are highly specialized and able to care for rare things in children, couldn’t apply by themselves. They had to apply in partnership with a center that could provide adult care as patients got older; otherwise, their care model would be incomplete. We’ve had some small victories already just by asking these questions and outlining this sort of approach. At one institution in the Great Plains, the director told us that he had been trying for years to get permission to hire someone who could make appointments across three different hospitals – a children’s hospital and two adult hospitals. He’d wanted to ensure that patients with rare and genetic diseases were seen in the appropriate places, and thanks to the NORD designation, he finally can. Now, regardless of age, the same office staff can handle the arrangements, and the patient will be scheduled in the right place.

You make clear that these are different from disease-specific centers of excellence – you specifically chose the 31 centers for their breadth of expertise. There’s no way to represent all 7,000 rare diseases equally, and disease-specific centers of excellence, which already exist for hemophilia, muscular dystrophy, cystic fibrosis, and some other conditions, have a very important role. We’re not aiming to compete with any other existing resources. What we are seeking to do is to fill the unmet need of, “What if there are no such designations for the disease that you’re concerned about?” Our goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.

The delay to diagnosis can be years in rare diseases. How can the network help speed up diagnoses?

With all these experts on different diseases, we hope to develop some better diagnostic algorithms within the network. Another thing we can do is to share resources. With 31 sites, everybody’s seeing patients with unknown diagnoses. Everyone is seeing patients for whom they would maybe like to get a whole genome done, or a whole exome done, but they are often encountering stiff resistance from insurance companies.

Meanwhile some sites, but not all 31, have multimillion-dollar grants to do sequencing and other kinds of advanced diagnostic tests to solve unknown cases. And there are people at those sites who say, “We need more samples. Can you get us samples from the other sites?”

One of the main things we aim to do is share information, including information about available diagnostic resources. We want all 31 sites to know which sites have funding and programs that enable them to study samples for other sites. We also want to know what criteria they’re putting on it. Someone might say: “I’ve got a grant to sequence genomes for people with unexplained seizures. Send me all your unexplained seizures.” Somebody else might have a grant for unexplained GI diseases. So, we want to put on our intranet a resource for the 31 sites, kind of a cookbook for – when if you can’t get it paid for by insurance, but you really think you need a particular special test – who might be able to do it for you within the network.

This would seem to benefit research across sites as well.

Yes, but we also want to share clinical advice and expertise for direct patient benefit. So, it doesn’t always have to fulfill the goals of a specific research project. For example, we might be able to create an undiagnosed patient quality improvement database across all 31 sites that could compliantly let Drs. X and Y know that they’re each seeing a patient with the same rare thing.

But let’s say you want to move the field forward by discovering a new disease. Rare genetic diseases are now being discovered at the rate of about 250 a year, so about 5 per week across the world. With two or three unrelated patients who have the same disease and a whole exome sequence, you can potentially discover a disease. Maybe you’ve found one unique patient with a genetic variant of possible significance, but you can’t be 100% sure, and you may not be able to convince your colleagues, or journal editors, until you find other cases. You need those two or three ultrarare patients. Within this network, a lot of sites want to share information about their ultrarare patients and be able to put together additional instances of the same thing, to prove that it is a real disease, to learn more about it and how to diagnose, manage, and treat it.

Part of the idea with a nationwide network is that patients aren’t going to have to move around among these centers of excellence, is that correct? They’re going to be seen at the closest ones, and it’s the expertise that is mobile.

Yes, that’s right. While we can’t eliminate the need for travel, what we are trying to do is increase the sharing of expertise, to improve results for patients while limiting the need for traveling very long distances. As a geneticist I’ve been on both the requesting and the receiving end of consultations with doctors at other sites, sometimes very far away, especially for ultrarare conditions for which any one physician’s experience is limited. We all try to honor these sorts of requests, but insurance doesn’t reimburse it and so hospitals don’t give doctors much credit for it.

We want to ultimately find ways to incentivize this type of collaboration. Hopefully we can get agreements with insurance companies to allow intersite consultations within our network, recognizing that they don’t want to pay for the patient to be seen out of state, but you also want the patient to get the best possible medical advice. This might require legislative changes in the long run. But what we can do more readily is create a culture within this network of mutual consultation and sharing of clinical experience. Outside of such a network, the idea of “cold calling” somebody, whom you may never have met, and asking them for help and free advice is a little bit of a bar, right? We want to lower that bar.

Can patients get telemedicine consults with physicians across the network?

NORD supports having telemedicine options for everybody regardless of diagnosis, rare or not, and we support legislation that would continue access and reimbursement for telemedicine post pandemic. I hope we can get that, or at least preserve telemedicine for rare diseases, for which there are often not enough, or sometimes not any, expert providers in the same state. Ultimately, we want patients to be able to get the expert assessments and advice they need. For rare diseases, that sometimes means battling back and forth with an insurance provider, seeking permission to see an expert clinician a thousand miles away. By sharing medical expertise, and through telemedicine when that’s allowed, we hope to reduce the need for that. But the telemedicine environment is still evolving and somewhat uncertain.

How will the network’s physician collaborations take place?

One of the important things NORD is providing to the network is an information technology setup and intranet across the 31 sites. That intranet is where center staff will go to access the network’s internal resources, including live and recorded case conferences. In those case conferences you can present a case you haven’t been able to solve. Experts you may have only heard of by reputation will now be streamed to your computer as part of the nationwide network. It benefits the patient because you get additional expert opinions, but it also benefits the physicians because we have this collegial space for discussion and learning. We’ll be linked by frequent meetings – some in person, most virtual – a common culture, and a common intranet.

On the intranet, we will also have a growing set of useful databases, links, and documents that are available to all members. These will be progressively updated with help from experts at the centers, so that clinicians can more directly learn from each other, instead of separately reinventing the wheel. The way things usually work, when you see a patient with an ultrarare condition that you’re not that familiar with, is that you tell them what little you can, then schedule them to come back in a few weeks. In the meantime, usually in your off time, you spend hours searching PubMed and other sources and you try to piece things together, to figure out what’s known that might help your patient. But imagine that this has already been figured out by someone else in the network. You can see on the network a list of articles the other expert read and found helpful in addressing this problem. And you then reach out directly to that other expert.

In recent months you’ve had one-on-one meetings with all 31 directors at the sites, and after that you convened 11 working groups. What are you trying to achieve?

Once the sites were chosen, we aimed to talk quickly and honestly about what everyone needed, what everyone saw as the biggest problems to tackle in rare diseases. Two things were very rewarding about those phone calls: one, all the centers were very enthusiastic, and two, they pretty much all agreed on what the key unmet needs are for rare disease patients and the practitioners trying to help them. So, we empaneled working groups of expert volunteers enthusiastic to work on each of those problems. These groups collectively comprise more than 200 volunteers – faculty, staff, and trainees – from the different sites nationwide. Each group is working on a key unmet need in rare diseases, and each group will be given its own space on our file-sharing platform, where they can share information and co-develop new ideas and documents. When something they produce is good enough to start to be a practice resource, such as a draft treatment guideline that the working group now wants to try in the real world, but it’s not yet ready to be published, they can share it and have it tested by all 31 sites through the dedicated intranet we are building for the network.

Jennie Smith is a freelance journalist specializing in medicine and health.

Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.

DIABETIC PERIPHERAL NEUROPATHY

The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.¹ Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.²

Diagnosis

Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.² Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.² In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.

4

Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.⁵ A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.⁶

Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.² A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.⁷

Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.² Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.

Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.⁸ A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.⁹ Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
 

Therapeutic options

The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.¹⁰ Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.

Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.¹¹ In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).¹¹ Further research is necessary to determine similar efficacy in human subjects.

Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.

Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.¹² Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.¹³ Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.³ The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.

Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O₂ species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.¹⁴ Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.¹⁵ Future testing in human subjects might reveal similarly positive effects.

Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B₁₂ – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.⁷¹

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.¹⁶ This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.¹⁷

Diagnostic tools and strategies

A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.

Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.¹⁸ This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.

Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.¹⁹ The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.¹⁹

Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.¹⁸

Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.¹⁸

Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.¹⁸

Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.

Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.¹⁸ Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.¹⁸

Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.⁶⁹ Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).⁶⁹ Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.

Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.²⁰ Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.²¹ This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.²¹

A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).²² The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.

NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).⁷⁰ NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.⁷⁰

SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.²³ Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.²⁴ JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.²⁵ IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.^23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.

Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.²⁷ Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.

These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.

Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.²⁸

With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.²⁹ In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).²⁹ The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.³⁰

Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O₂ species, regulates ion channels, and protects axons and the myelin sheath.^31,32

Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.²⁸ A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.³³

TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).³³ However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.

Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.^34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.³⁶

Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).³⁷ However, more research is needed before implementing their use in point-of-care settings.
 

AUTOIMMUNE PERIPHERAL NEUROPATHY

Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.

Guillain-Barré syndrome: Diagnostic tools and strategies

Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).³⁸ In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.³⁹

It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.⁴⁰ However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.⁴¹ A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.

Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.⁴²

Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.⁴³ Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
 

Guillain-Barré syndrome: Therapeutic options

The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.⁴⁴ Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.⁴⁰ Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.⁴⁵

Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.

ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.⁴⁶ Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r² = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.⁴⁰

ANX005 is entering phase 2 trials, which are expected to be completed in 2023.⁴⁷

Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.⁴⁸ Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.

A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:

• Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
• Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.

Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.⁵⁰

Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.⁵¹

IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.⁵²

Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies

CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.⁵³

Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.⁵⁴ Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.⁵⁵

Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.⁵⁶

Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.⁵⁷ Larger-scale studies are needed to further test the efficacy of this method.
 

Chronic inflammatory demyelinating polyneuropathy: Therapeutic options

First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.⁴⁵

Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.

Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.^58,59

Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”⁶⁰ These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.⁶¹ Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.⁶² Phase 2 trials are recruiting, with a projected primary completion in 2023.
 

INFECTION-INDUCED PERIPHERAL NEUROPATHY

Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.⁶³ Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.

HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.⁶⁴ The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.⁶⁵ Symptoms include loss of sensory properties, neuropathic pain, and allodynia.⁶⁶

Diagnostic tools and strategies

Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.⁶⁶

Therapeutic options

Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.⁶⁷

Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.⁶⁶ This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.

Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.

The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.⁶⁴ This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
 

CRYPTOGENIC SENSORY POLYNEUROPATHY

Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.

Diagnostic tools and strategies

Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.⁶⁸

Therapeutic options

There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.⁶⁸ Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.³

Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.

Summing up

The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:

Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.³ Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.¹⁰

Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,²² and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.^23-26

Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.²⁹ Animal models have shown progress studying antioxidant agents, such as amifostine³¹ and calmangafodipir,³² which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.

Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;³⁷ more studies must be completed before these agents can be established as effective therapy.

Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.^47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.⁴⁰ Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.^58-60

Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.⁶⁶ Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.⁶¹

Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.³
 

Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.

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Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.

DIABETIC PERIPHERAL NEUROPATHY

The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.¹ Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.²

Diagnosis

Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.² Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.² In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.

4

Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.⁵ A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.⁶

Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.² A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.⁷

Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.² Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.

Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.⁸ A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.⁹ Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
 

Therapeutic options

The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.¹⁰ Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.

Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.¹¹ In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).¹¹ Further research is necessary to determine similar efficacy in human subjects.

Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.

Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.¹² Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.¹³ Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.³ The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.

Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O₂ species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.¹⁴ Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.¹⁵ Future testing in human subjects might reveal similarly positive effects.

Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B₁₂ – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.⁷¹

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.¹⁶ This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.¹⁷

Diagnostic tools and strategies

A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.

Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.¹⁸ This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.

Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.¹⁹ The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.¹⁹

Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.¹⁸

Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.¹⁸

Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.¹⁸

Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.

Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.¹⁸ Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.¹⁸

Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.⁶⁹ Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).⁶⁹ Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.

Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.²⁰ Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.²¹ This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.²¹

A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).²² The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.

NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).⁷⁰ NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.⁷⁰

SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.²³ Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.²⁴ JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.²⁵ IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.^23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.

Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.²⁷ Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.

These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.

Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.²⁸

With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.²⁹ In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).²⁹ The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.³⁰

Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O₂ species, regulates ion channels, and protects axons and the myelin sheath.^31,32

Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.²⁸ A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.³³

TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).³³ However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.

Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.^34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.³⁶

Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).³⁷ However, more research is needed before implementing their use in point-of-care settings.
 

AUTOIMMUNE PERIPHERAL NEUROPATHY

Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.

Guillain-Barré syndrome: Diagnostic tools and strategies

Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).³⁸ In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.³⁹

It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.⁴⁰ However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.⁴¹ A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.

Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.⁴²

Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.⁴³ Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
 

Guillain-Barré syndrome: Therapeutic options

The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.⁴⁴ Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.⁴⁰ Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.⁴⁵

Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.

ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.⁴⁶ Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r² = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.⁴⁰

ANX005 is entering phase 2 trials, which are expected to be completed in 2023.⁴⁷

Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.⁴⁸ Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.

A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:

• Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
• Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.

Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.⁵⁰

Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.⁵¹

IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.⁵²

Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies

CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.⁵³

Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.⁵⁴ Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.⁵⁵

Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.⁵⁶

Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.⁵⁷ Larger-scale studies are needed to further test the efficacy of this method.
 

Chronic inflammatory demyelinating polyneuropathy: Therapeutic options

First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.⁴⁵

Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.

Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.^58,59

Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”⁶⁰ These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.⁶¹ Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.⁶² Phase 2 trials are recruiting, with a projected primary completion in 2023.
 

INFECTION-INDUCED PERIPHERAL NEUROPATHY

Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.⁶³ Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.

HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.⁶⁴ The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.⁶⁵ Symptoms include loss of sensory properties, neuropathic pain, and allodynia.⁶⁶

Diagnostic tools and strategies

Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.⁶⁶

Therapeutic options

Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.⁶⁷

Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.⁶⁶ This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.

Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.

The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.⁶⁴ This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
 

CRYPTOGENIC SENSORY POLYNEUROPATHY

Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.

Diagnostic tools and strategies

Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.⁶⁸

Therapeutic options

There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.⁶⁸ Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.³

Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.

Summing up

The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:

Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.³ Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.¹⁰

Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,²² and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.^23-26

Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.²⁹ Animal models have shown progress studying antioxidant agents, such as amifostine³¹ and calmangafodipir,³² which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.

Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;³⁷ more studies must be completed before these agents can be established as effective therapy.

Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.^47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.⁴⁰ Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.^58-60

Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.⁶⁶ Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.⁶¹

Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.³
 

Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.

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37. Aydin Köker S et al. Effect of pyridoxine plus pyridostigmine treatment on vincristine-induced peripheral neuropathy in pediatric patients with acute lymphoblastic leukemia: A single-center experience. Neurol Sci. 2021 Sep;42(9):3681-6. doi: 10.1007/s10072-020-04970-w.

38. Bourque PR et al. Autoimmune peripheral neuropathies. Clin Chim Acta. 2015 Sep 20;449:37-42. doi: 10.1016/j.cca.2015.02.039.

39. Paparounas K. Anti-GQ1b ganglioside antibody in peripheral nervous system disorders: Pathophysiologic role and clinical relevance. Arch Neurol. 2004 Jul;61(7):1013-6. doi: 10.1001/archneur.61.7.1013.

40. Dalakas MC. Autoimmune peripheral neuropathies, in Rich RR et al., eds., “Clinical Immunology.” 5th ed, (Amsterdam: Elsevier, 2019, pp. 903-915.e1). doi: 10.1016/B978-0-7020-6896-6.00067-3

41. Leonhard SE et al. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15(11):671-83. doi: 10.1038/s41582-019-0250-9.

42. Razali SNO et al. Serial peripheral nerve ultrasound in Guillain–Barré syndrome. Clin Neurophysiol. 2016 Nov;127(2):1652-6. doi: 10.1016/j.clinph.2015.06.030.

43. Gallardo E et al. Spinal nerve involvement in early Guillain-Barré syndrome: A clinico-electrophysiological, ultrasonographic and pathological study. Clin Neurophysiol. 2015 Apr;126(4):810-9. doi: 10.1016/j.clinph.2014.06.051.

44. Islam Z et al. Inhibition of C1q, initiator of the classical complement cascade, by ANX005 for the treatment of Guillain–Barré syndrome: Results from a phase 1b study (763). Neurology. 2020 Apr;94(15 Suppl):763.

45. Hughes R et al.; FORCIDP Trial Investigators. Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): A double-blind, multicentre, randomised controlled trial. Lancet Neurol. 2018 Aug;17(8):689-98. doi: 10.1016/S1474-4422(18)30202-3.

46. Lansita JA et al. Nonclinical development of ANX005: A humanized anti-C1q antibody for treatment of autoimmune and neurodegenerative diseases. Int J Toxicol. 2017 Nov/Dec;36(6):449-62. doi: 10.1177/1091581817740873.

47. Annexon Inc. A randomized, double-blind, placebo-controlled phase 2/3 study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ANX005 in subjects with Guillain–Barré syndrome. ClinicalTrials.gov Identifier: NCT04701164. Updated Jan 8, 2021. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04701164.

48. Halstead SK et al. Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model. Brain. 2008 May;131(Pt 5):1197-1208. doi: 10.1093/brain/awm316.

49. Misawa S et al. Safety and efficacy of eculizumab in Guillain-Barré syndrome: A multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018 Jun;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

50. Alexion Pharmaceuticals. A phase 3, prospective, multicenter, double blind, randomized, placebo-controlled study to evaluate the efficacy and safety of eculizumab in patients with Guillain–Barré syndrome (GBS). ClinicalTrials.gov Identifier: NCT04752566. Updated Feb 18, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04752566.

51. Tzachanis D et al. Successful treatment of refractory Guillain–Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia. Acta Haematol. 2014 Aug;132(2):240-3. doi: 10.1159/000358292.

52. Satkowiak K, Smith AG. Guillain-Barré syndrome, in Roos KL, ed. “Emergency Neurology.” (Springer, Cham, 2021, pp. 225-50). Accessed Feb 23, 2022. https://doi.org/10.1007/978-3-030-75778-6_12.

53. Gogia B et al. Chronic inflammatory demyelinating polyradiculoneuropathy, in “StatPearls [Internet].” (Treasure Island (Fla.): StatPearls Publishing; 2022 Jan). Updated Nov 22, 2021. Accessed Feb 23, 2022. www.ncbi.nlm.nih.gov/books/NBK563249.

54. Allen JA et al. Challenges in the diagnosis of chronic inflammatory demyelinating polyneuropathy. Brain Behav. 2018 Feb;8(3):e00932. doi: 10.1002/brb3.932.

55. Stino AM et al. Chronic inflammatory demyelinating polyradiculoneuropathy-diagnostic pitfalls and treatment approach. Muscle Nerve. 2021 Feb;63(2):157-69. doi: 10.1002/mus.27046.

56. Ginsberg MR et al. Using and interpreting electrodiagnostic tests. Cleve Clin J Med. 2020 Nov 2;87(11):671-82. doi: 10.3949/ccjm.87a.19154.

57. Capodivento G et al. CSF sphingomyelin: A new biomarker of demyelination in the diagnosis and management of CIDP and GBS. J Neurol Neurosurg Psychiatry. 2021;92(3):303-10. doi: 10.1136/jnnp-2020-324445.

58. Shimizu S et al. Efficacy and safety of rituximab in refractory CIDP with or without IgG4 autoantibodies (RECIPE): Protocol for a double-blind, randomized, placebo-controlled clinical trial. JMIR Res Protoc. 2020 Jan 4;9(4):e17117. doi: 10.2196/17117.

59. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349(9047):225-30.

60. Zuercher AW et al. Next-generation Fc receptor–targeting biologics for autoimmune diseases. Autoimmun Rev. 2019 Oct;18(10):102366. doi: 10.1016/j.autrev.2019.102366.

61. Sesarman A et al. The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases. Cell Mol Life Sci. 2010 Aug;67(15):2533-50. doi: 10.1007/s00018-010-0318-6.

62. Ulrichts P et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018 Oct;128(10):4372-86. doi: 10.1172/JCI97911.

63. Peripheral neuropathy [symptoms and causes]. Mayo Clinic [Internet]. Accessed Feb 23, 2022. http://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061.

64. Maharaj SS, Yakasai AM. Does a rehabilitation program of aerobic and progressive resisted exercises influence HIV-induced distal neuropathic pain? Am J Phys Med Rehabil. 2018 May;97(5):364-9. doi: 10.1097/PHM.0000000000000866.

65. Fields JA et al. Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice. Sci Rep. 2019 Nov 20;9(1):17158. doi: 10.1038/s41598-019-53466-x.

66. Han MM et al. Prevention of HIV-1 TAT protein-induced peripheral neuropathy and mitochondrial disruption by the antimuscarinic pirenzepine. Front Neurol. 2021 Jun 15;12:663373. doi: 10.3389/fneur.2021.663373.

67. Rozzi SJ et al. Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. Cell Death Discov. 2018;4:8. doi: 10.1038/s41420-017-0013-6.

68. Pasnoor M et al. Cryptogenic sensory polyneuropathy. Neurol Clin. 2013 May;31(2):463-76. doi: 10.1016/j.ncl.2013.01.008.

Peripheral neuropathy is becoming an increasing focal point for clinicians when treating patients because of the plethora of causes to which the disorder has been attributed. Characterized by damage to the peripheral nervous system, peripheral neuropathy causes sharp, burning pain; numbness of the extremities that can travel proximally; muscle weakness; and an overall diminished quality of life. Rather than being a self-developing disease, peripheral neuropathy has mostly been identified as a symptom of causative disorders and therapeutic agents – making prevention and treatment extremely important for patients and providers.

DIABETIC PERIPHERAL NEUROPATHY

The most common cause of peripheral neuropathy is diabetes mellitus. Diabetic peripheral neuropathy (DPN) is a symmetrical, length-dependent neuropathy that affects more than 50% of type I and type II diabetes patients.¹ Not only is DPN an initiating factor of foot ulcers and nontraumatic lower-limb amputation, but it also leads to a severely lower quality of life, financial burden, and increased risk of death after major surgical procedures.²

Diagnosis

Nerve-conduction studies are the preferred diagnostic tool for DPN; however, these studies are costly and difficult to conduct in a clinical setting.² Currently, such diagnostic tools as the 10-g monofilament and tuning fork are more commonly utilized to detect loss of protective foot sensation to decrease the risk of foot ulceration.² In addition, other common aspects of diagnosing DPN include assessment of symptoms in the patient’s hands or feet and patient-reported symptoms.

4

Neuropad, a 10-minute test, measures foot plantar-surface sweat production, indicated by a cobalt compound color change on the device. The test is advantageous because it is highly sensitive – 73% more sensitive than DPNCheck – and does not rely on patient response or require operator training.⁵ A study of Neuropad showed that a drier foot and, therefore, increased risk of foot ulceration correlated with greater abnormal readings on the device, which might indicate onset of more severe DPN in the future.⁶

Sudoscan measures sudomotor function in 3 minutes through an electrochemical reaction between stimulated sweat glands and electrodes.² A study performed in China in patients with type 2 diabetes (n = 394) showed that electrical conductance in the feet is associated with increasing risk and severity of symptoms of DPN in asymptomatic patients (r = 0.98 [95% confidence interval, 0.962-0.993]; P < .01) and might serve as a biomarker of DPN.⁷

Although these three techniques present favorable data, each is a nerve conduction study that can access only small-fiber nerves. Additional testing is required for larger-fiber nerves that are also affected by DPN.² Also, some of the studies of these devices have high heterogeneity and a small sample size. Further research utilizing these three methods should include larger sample sizes to appropriately assess any clinically significant patient outcomes.

Corneal confocal microscopy (CCM), another potential technique for DPN screening, is a noninvasive ophthalmic device for assessing corneal small-fiber nerves. A study of patients with diabetes or obesity or both (n = 35) showed high reproducibility of corneal-nerve pathology identification using CCM.⁸ A larger-scale study showed that CCM can detect a reduction in corneal-nerve parameters in DPN patients, as well as in patients who have yet to develop DPN – thus demonstrating the technique’s ability to detect both early subclinical and established DPN.⁹ Once CCM is approved as a point-of-care device, it might provide a reliable, sensitive screening method for DPN as an early-intervention tool.
 

Therapeutic options

The three principal types of treatment for DPN are tricyclic antidepressants, anticonvulsants, and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs). Only three medications are Food and Drug Administration (FDA) approved for the treatment of DPN: pregabalin, duloxetine, and the recently approved capsaicin patch. Some opioid analgesics, including extended-release tapentadol, are FDA approved for DPN-associated neuropathic pain; however, evidence of their efficacy is questionable, and they present a risk of addiction.¹⁰ Here, we focus on potential treatments for DPN and DPN-associated neuropathic pain.

Cinacalcet. Several potential treatments have been studied for alleviating DPN symptoms after progression. Cinacalcet is a calcimimetic agent that activates the adenosine monophosphate-activated protein kinase–endothelial nitric oxide synthase pathway, which mediates DPN development. The drug has shown evidence of improving sensorimotor function and restoring nerve function in human Schwann cells expressed in diabetes-induced mice.¹¹ In these animal models, cinacalcet improved tactile response when interventional mice were compared with a control group (P < .01).¹¹ Further research is necessary to determine similar efficacy in human subjects.

Traditional Chinese medicine. Recent studies have focused on traditional Chinese medicine and practice, such as acupuncture and moxibustion, for DPN.

Moxibustion is the technique of burning moxa floss (a plant also known as mugwort) on different points on the body, which is thought to alleviate disease. In a study performed on rats, moxibustion increased nerve velocity (P < .05) and preserved sciatic-nerve ultrastructure.¹² Research on the use of moxibustion is preliminary. A meta-analysis of available data found that all clinical studies took place in China, and results were therefore subject to high heterogeneity and small sample size.¹³ Previously, a lack of high-quality data prevented moxibustion from being considered a potential treatment.³ The technique has demonstrated potential benefit, but larger-scale and more rigorous studies must be utilized to verify its clinical efficacy.

Quercetin. This common dietary flavonoid is in development. In rat models with induced DPN, treatment produced significant neuroprotective effects, such as rescued mechanical withdrawal threshold, lowered nerve densities (P = .0378), and rescued lowered levels of reactive O₂ species (P < .0001), which contribute to neurotoxicity in many peripheral neuropathies.¹⁴ Another study of the anti-inflammatory effects of quercetin in rat models found significant lowering of inflammatory factors, including proteins encoded by toll-like receptor 4 and MyD88, and protein transcription factor nuclear factor kappa B (P < .001), which can be beneficial in the treatment of DPN.¹⁵ Future testing in human subjects might reveal similarly positive effects.

Vitamin B. A systematic review examined the therapeutic effects of vitamin B supplementation on DPN. Through a meta-analysis on 14 studies (N = 997), it was revealed that statistically significant improvements in pain and electrophysiological sensory outcomes were observed after vitamin B supplementation. However, the majority of the studies included in the analysis utilized combination therapies with different vitamins (such as vitamin D) and other vitamin B types. Furthermore, deficiencies in B vitamins – especially folic acid and vitamin B₁₂ – have been observed in diabetic patients, and may be the potential cause of DPN in them. The validity of the studies and their findings are weakened by this observation. Therefore, the clinical efficacy of individual B vitamin supplements must be evaluated in long-term, larger scale future studies that exclude those with B vitamin deficiency and DPN to minimize potential error.⁷¹

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Another cause of peripheral neuropathy has been directly linked to particular chemotherapeutic agents. Platinum-based agents have been widely accepted as an ideal solution for slowing tumor progression; however, it has been established that platinum adducts within DNA are the cause of neuronal degeneration – specifically in dorsal-root ganglion neurons of the peripheral nervous system. In a 2010 meta-analysis in the United States, the prevalence of chemotherapy-induced peripheral neuropathy (CIPN) was observed to range from 65% to 75%, depending on the platinum-based agent.¹⁶ This problem is often dose-limiting and can lead to cessation of treatment, causing patients physical and financial harm. CIPN can be acute or chronic, and symptoms affect motor, sensory, and autonomic function, which can lead to reduced quality of life.¹⁷

Diagnostic tools and strategies

A variety of avenues can be taken to assess whether a patient has CIPN. Because peripheral neuropathy is often subjective, it has been recommended that clinicians use patient-reported outcome measures in this setting, in the form of a questionnaire.

Common toxicity criteria. The most conventional measure of CIPN is the National Cancer Institute’s Common Toxicity Criteria, which grades severity of adverse effects on a scale of 1 to 5 and has been found to be statistically valid.¹⁸ This questionnaire assesses a patient’s neuropathic pain score and sensory deficits, and can detect other potential adverse findings, such as neutropenia.

Total neuropathy score. This commonly used questionnaire measures subjective autonomic, sensory, and motor symptoms on a scale of 0 to 4 for each item, with the individual item scores then summed. A score > 5 indicates CIPN.¹⁹ The tested validity of this measure shows that it has an inter-rater reliability of 0.966 and an intra-rater reliability of 0.986.¹⁹

Other questionnaires. The Neuropathy Screening Questionnaire, Treatment-Induced Neuropathy Assessment Scale, and Chemotherapy-Induced Peripheral Neuropathy Assessment Tool have been identified as means of understanding what a patient experiences following neurotoxic chemotherapy.¹⁸

Pain caused by CIPN can also be assessed with one of several general scales, such as the Neuropathic Pain Scale for Chemotherapy-Induced Neuropathy (NPS-CIN), which identifies a patient’s level of pain on a scale from 0 to 4 on six items: intensity, unpleasantness, sharpness, depth, numbness, and tingling. This scale has been found to be reliable.¹⁸

Other scales that can be used are the Neuropathic Pain Symptom Inventory, Patient-Reported Outcomes Measurement Information System: Pain Quality Neuro, and Leeds Assessment of Neuropathic Symptoms and Signs.¹⁸

Other diagnostic tests. Tests to determine a chemotherapy patient’s functional ability regarding their extremities include postural stability tests, the Timed Up and Go (TUG) test, the Fullerton Advance Balance (FAB) Scale, the 6-minute walk test, and the grooved pegboard test.

Nerve conduction studies have been identified as useful tools to assess the physiologic function of fibers, but are costly and used most often in research settings.¹⁸ Quantitative sensory testing and the Bumps test are used to assess threshold capacities for varying sensations. Nerve-imaging tools, such as high-resolution ultrasonography, magnetic resonance neurography, and positron emission and computed tomography, have been found to be successful in identifying nerve damage.¹⁸

Additionally, the accumulation of mitochondrial DNA (mtDNA) in the blood has been identified as a potential biomarker for CIPN following animal trials on rats.⁶⁹ Researchers conducted a double-blind trial where healthy rats were given doses of paclitaxel, oxaliplatin, and bortezomib and compared to vehicle-treated rats. Researchers found that there was a correlation between the onset of CIPN and levels of mtDNA, with 1-2-fold increases of mtDNA found in paclitaxel and oxaliplatin treated patients (P < 0.01).⁶⁹ Dysfunctional mitochondria can cause an increase in the activity of reactive oxygen species which results in damage to mtDNA; and abnormal bioenergetics, which may lead to irregular ATP production and result in cellular damage.

Navitoclax. The antineoplastic agent cisplatin is used to treat a variety of cancers, including ovarian, lung, head and neck, testicular, and bladder.²⁰ Using single-cell RNA sequencing of dorsal-root ganglion cells in mouse models that have been given human equivalent doses of cisplatin to induce peripheral neuropathy, a study identified that the drug was upregulating the cyclin-dependent kinase inhibitor 1A gene (CDKN1A) and leading to overproduction of its product, the p21 protein.²¹ This is due to a cellular response to DNA damage that causes the dorsal-root ganglion sensory neuron to change into a senescence-like state to survive. Subsequently, accumulation of senescent sensory neurons correlates with induction of neuropathic pain and peripheral neuropathy. It has been established, in mouse models, that removing senescent cells has the potential to reduce or reverse peripheral neuropathy associated with cisplatin treatment.²¹

A study induced irreversible CIPN using cisplatin on mice that were subsequently treated with antineoplastic agent navitoclax (n = 5) or vehicle (n = 10). Using navitoclax, a broad-spectrum senolytic agent, the study examined the dorsal-root ganglia of the mice and found that CIPN was reversed following clearance of senescent cells, with baseline mechanical thresholds able to be reestablished without difference, compared with the control group (P = .7734).²² The investigators found that clearance of senescent cells using navitoclax proved a promising avenue toward mitigating CIPN. More studies should be completed to validate this treatment as an effective preventive.

NGF Monoclonal Antibody (Tanezumab). Tanezumab has been identified as a potential analgesic for CIPN having observed success during animal trials. This monoclonal antibody targets the NGF-TrkA pathway in a dose-dependent manner which results in a reduction of neuronal sensitivity and subsequently neuropathic pain (P < 0.05).⁷⁰ NGF is a peripheral pain mediator that has functional properties relating to inflammation and neuropathy. Therefore, by targeting this protein and inhibiting its activation, patients could potentially see a dramatic improvement in their quality of life following a CIPN diagnosis. This potential analgesic was observed to be successful for a variety of chemotherapeutic agents including cisplatin, vincristine, and paclitaxel.⁷⁰

SASP inhibitors. A second possible approach to neutralizing senescent cells would be by inhibiting the senescence-associated secretory phenotype (SASP). This could be accomplished through the use of nuclear factor kappa B inhibitors, mammalian target of rapamycin (mTOR) inhibitors, bromodomain and extra-terminal (BET) inhibitors, and inhibitors of secretory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF) alpha.²³ Rapamycin, an mTOR inhibitor that is already used in clinical settings, has been found to reduce the inflammatory effects of senescent cells, expanding the lifespan of mice.²⁴ JQ1, OTX015, and ARV825 are BET inhibitors that have been found to block bromodomain-containing protein 4, thus inducing senescent cell death.²⁵ IL-6 inhibitors (for example, tocilizumab) and TNF alpha inhibitors (for example, adalimumab) are already used clinically and can mitigate the effects of SASP.^23,26 However, further studies are needed to examine potential adverse effects of this type of therapy.

Mitigation of oxaliplatin adverse effects. This platinum-based chemotherapeutic agent associated with peripheral neuropathy is primarily used to treat colorectal cancer and digestive-tract malignancies.²⁷ Oxaliplatin-induced peripheral neuropathy (OIPN) can be acute or chronic, and causes neuropathic pain, autonomic nerve dysfunction, and hypersensitivity to cold, which lead to abnormal nervous system effects, such as peripheral paresthesia.

These symptoms derive from oxaliplatin’s effects on a variety of cellular mechanisms, and differ in chronic and acute OIPN. Acute OIPN includes abnormal changes to sodium, potassium, calcium, and transient receptor potential channels, which lead to dysregulation and dysfunction in peripheral neurons; glia activation associated with dysregulation of pain modulation, by reducing thresholds; and upregulation of the octamer-binding transcription factor (OCT) protein.

Chronic OIPN has been associated with damage to nuclear DNA by platinum adducts, mitochondrial dysfunction (due to oxidative stress), and neuroinflammation caused by glia activation and gut microbiota.²⁸

With increased understanding regarding cellular mechanisms affected in OIPN, treatment options are being established to prevent or reduce its effects. A treatment being tested for the treatment of OIPN is the serotonin and norepinephrine reuptake inhibitor (SSNRI) antidepressant duloxetine.²⁹ In a clinical trial of 40 patients with gastrointestinal cancer, duloxetine was found to reduce cold sensitivity (P = .001), tingling or discomfort of hands (P < .002) and feet (P = .017), and peripheral neuropathic pain (P = .001), and was found to prevent paresthesia (P = .025).²⁹ The SNRI antidepressant venlafaxine has also shown that it can alleviate neuropathic pain and motor neuropathy in clinical trials.³⁰

Antioxidant agents, such as amifostine and calmangafodipir, have also been identified as possible preventive measures against OIPN. Amifostine prevents neuronal hyperactivation and nitrosative stress, while calmangafodipir modulates reactive O₂ species, regulates ion channels, and protects axons and the myelin sheath.^31,32

Treatments such as riluzole, lidocaine, and pregabalin have all shown promise in reducing the effects of OIPN by their action on potassium, sodium, and calcium channels, respectively.²⁸ A study conducted on mice (n = 565) with OIPN found that riluzole effectively mitigated motor and sensory deficits associated with the use of oxaliplatin.³³

TREK-1 and TRAAK, potassium channels that are important for thermal and motor sensitivity, and that act as silencing mechanisms to excitatory stimuli, were shown to degenerate following oxaliplatin treatment, leading to hypersensitivity. Riluzole performs its therapeutic function by activating TREK-1 and TRAAK channels and blocking excessive accumulation of glutamate. Following riluzole treatment, mice were observed to show a significant reduction in sensorimotor deficits. Interestingly, riluzole also aided in reducing depression associated with oxaliplatin (P < .01).³³ However, more studies are necessary to ensure the safety and efficacy of riluzole in humans.

Pyridoxine, pyridostigmine for vincristine-induced peripheral neuropathy. Vinca alkaloids have also been identified as chemotherapeutic agents that induce peripheral neuropathy. One such agent, vincristine, which is used primarily to treat leukemia and brain cancer, has been observed to cause peripheral neuropathy, including motor, autonomic, and sensory symptoms, such as abnormal gait, mechanical allodynia, paresthesia, ptosis, and obstipation, and altered perception of stimuli.^34,35 These symptoms are caused primarily by the ability of vincristine to activate neuroinflammatory mechanisms in dorsal-root ganglia. This is caused by activation of nucleotide-binding oligomerization domain 3 (NLRP3)-dependent release of IL-1b and subsequent cleavage of gasdermin D and caspase-1 in macrophages (observed in mouse models). Vincristine activates the NLRP3 signaling cascade that results in production of proinflammatory cytokines, thus inducing symptoms of peripheral neuropathy.³⁶

Pyridoxine and pyridostigmine have been introduced as potential treatments for vincristine-induced peripheral neuropathy. Following a clinical trial of pediatric acute lymphoblastic leukemia patients, a study of 23 patients with vincristine-induced peripheral neuropathy found statistical validity for using pyridoxine and pyridostigmine because the drugs improved the neuropathy score (P < .001).³⁷ However, more research is needed before implementing their use in point-of-care settings.
 

AUTOIMMUNE PERIPHERAL NEUROPATHY

Autoimmune peripheral neuropathies (APNs) occur when the immune system targets peripheral nervous system and its various cells. Although there is a wide range of conditions in this category of peripheral neuropathy, the two most common types – Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) – have been targeted for clinical research.

Guillain-Barré syndrome: Diagnostic tools and strategies

Guillain-Barré syndrome encompasses a variety of acute inflammatory polyneuropathies, including axonal motor, sensory, and autonomic neuropathies and Miller Fisher syndrome (MFS).³⁸ In particular, the anti-GQ1b ganglioside antibody is considered archetypical in APNs because it is detected in MFS patients and not found in normal and disease-control samples, which makes it a good clinical marker.³⁹

It is difficult to distinguish GBS from CIDP because the time frame of onset of maximum deficit of neuropathy – 4 weeks – can overlap with subacute CIDP symptoms.40 Current diagnosis is based on elevated levels of cerebrospinal fluid (CSF) proteins, which can increase fourfold 6 weeks into the early phase of disease, and nerve conduction studies.⁴⁰ However, electrodiagnostic readings and CSF protein levels are normal in 30% to 50% of patients in the first week after onset of disease and must be repeated in weeks that follow.⁴¹ A major disadvantage in the workup of suspected GBS is that the syndrome can be confirmed only several weeks after onset of symptoms.

Ultrasonography. A potential new diagnostic tool is serial peripheral nerve ultrasonographic (US) imaging. A pilot study of GBS patients (n = 16) showed that US can detect enlarged nerve cross-sections in median, ulnar, and sural nerves in the first 3 weeks of disease. Imaging performance was consistent with that of nerve conduction studies, and was advantageous because US is easier to perform and for patients to undergo.⁴²

Spinal inflammation. Another study hints at the importance of spinal-root inflammation as an early indicator of disease, especially when nerve conduction study readings are normal.⁴³ Further research is needed to demonstrate the clinical efficacy of this diagnostic method in larger population groups.
 

Guillain-Barré syndrome: Therapeutic options

The standard of care for GBS in the United States is intravenous immunoglobulin (IVIG) therapy and plasmapheresis, but there is no FDA-approved treatment.⁴⁴ Although the two treatments have been shown to be equally effective in early stages of disease, early relapses can occur with both. One study found that 20% of patients who underwent plasmapheresis relapsed.⁴⁰ Because nearly 50% of GBS patients do not respond to IVIG or plasmapheresis, the need is urgent for new therapies to decrease the risk of permanent disability.⁴⁵

Antibody therapy. Recent developments include the use of monoclonal antibodies against GBS. ANX005 is an immunoglobulin G4 recombinant antibody that inhibits complement component 1q (C1q). Activation of this protein triggers the classical complement cascade, a natural part of the innate immune system that is nonetheless inappropriately activated in some autoimmune diseases, leading to neurodegeneration as a consequence of tissue damage.

ANX005 was found to have high-binding affinity to C1q in human, rat, cynomolgus monkey, and dog sera in nonclinical trials, and demonstrated low cross-reactivity despite being a plasma protein present throughout human tissue. Furthermore, studies show that ANX005 can deplete C1q completely in the CSF of monkeys.⁴⁶ Phase 1b clinical trials in Bangladesh with GBS patients (n = 23) 18 to 58 years of age against a placebo group (n = 8) indicate that treatment is well tolerated. Drug-related serious adverse events were lacking and subjects’ GBS-Disability Score improved compared with placebo controls at week 1 (r² = 0.48; P < .0001) and week 8, when an improvement of three or more in the score was observed.⁴⁰

ANX005 is entering phase 2 trials, which are expected to be completed in 2023.⁴⁷

Eculizumab. This promising treatment is a monoclonal antibody against C5 convertase, an enzyme that catalyzes formation of C5b-9, a membrane attack complex in nerve membranes. Studies in mouse models showed that treatment could significantly improve symptoms of terminal motor neuropathy and completely block formation of membrane attack complexes.⁴⁸ Rats in this study were paralyzed by anti-GQ1b antibodies to emulate GBS pathogenesis.

A double-blind, placebo-controlled phase 2 clinical trial in Japan enrolled 34 patients (23 assigned to receive eculizumab; 11, to placebo); all were 18 years old or older and could not walk independently (3-5 on the GBS functional grading scale). Results showed that:

• Sixteen percent more patients receiving eculizumab treatment (n = 14; 42-78 years) than in the placebo group (n = 5; 20-73 years) could walk independently after 4 weeks.
• Fifty-six percent more patients in the functional group (n = 17; 52-90 years) than in the placebo group (n = 2; 20-52 years) could run after 6 months.49 While it is noted that the first portion of the trial failed to meet the predefined significance level, its long-term effects are observed to have therapeutic potential.

Eculizumab is in phase 3 clinical trials with primary data to be released in October 2022.⁵⁰

Alemtuzumab, which inhibits the CD52 gene, was found to alleviate symptoms and restore strength in a rapidly deteriorating patient with MFS and chronic lymphocytic leukemia. By week 4 of treatment, anti-GQ1B antibodies were eliminated. However, the cause of this patient’s MFS is unclear; recovery might have been the result of multiple factors.⁵¹

IgG inhibition. Additional ongoing studies include therapies geared toward the neonatal Fc receptor as a potential clinical target for IgG inhibition.⁵²

Chronic inflammatory demyelinating polyneuropathy (CIDP): Diagnostic tools and strategies

CIDP is the most common chronic APN and shares many similarities with GBS but differs in its responsiveness to corticosteroids, prognosis, and more. Lack of consensus on diagnostic criteria for CIDP has led to reliance on nerve conduction studies and clinical findings for making the diagnosis.⁵³

Guidelines. European Federation of Neurological Societies/Peripheral Nerve Society guidelines have high sensitivity (81%) and specificity (96%) and are utilized as diagnostic criteria for CIDP; however, a survey found that these criteria may be underutilized in clinical practice – which might contribute to a high misdiagnosis rate.⁵⁴ Furthermore, although current diagnostic methods are dependent on CSF proteins, this disease is lacking a diagnostic biomarker, leading to easy overdiagnosis and unnecessary immunotherapy.⁵⁵

Electrodiagnostic testing, which is often used, is limited because it cannot evaluate small-fiber nerves, cannot access the CNS adequately, and does not provide a specific diagnosis.⁵⁶

Sphingomyelin in CSF. Recently, a study in Italy explored the potential of CSF sphingomyelin as a biomarker for CIDP and for GBS. Findings reveal that sphingomyelin levels can be used to diagnose more than 80% of APN cases in the clinical setting. Different levels were identified in GBS, acute inflammatory demyelinating polyneuropathy, and typical and atypical CIDP patients. Additionally, sphingomyelin showed potential to diagnose the correct stage of disease. An increase in sphingomyelin in relapsing CIDP patients was noted, compared with what was seen in controls and stable CIDP patients.⁵⁷ Larger-scale studies are needed to further test the efficacy of this method.
 

Chronic inflammatory demyelinating polyneuropathy: Therapeutic options

First-line therapy for CIDP comprises prednisone, 60-100 mg/d, plasmapheresis, and IVIG, all of which have proved effective. Some patients respond better to one treatment than to others40; some have subpar response to all these treatments and are categorized as having refractory CIDP.⁴⁵

Although there are no newly approved treatments for CIDP, several show promise in ongoing clinical trials.

Rituximab is an anti-CD20 monoclonal antibody being studied in two phase 2 clinical trials of efficacy for refractory CIDP with IgG4 autoantibodies, after showing potential efficacy.^58,59

Efgartigimod is an Fc fragment that blocks the neonatal Fc receptor, prevents lysosome degradation of IgGs, and thus allows them to be “recycled.”⁶⁰ These autoantibodies are crucial in disease pathology because lowering their concentration provides effective therapy.⁶¹ Phase 1 trials showed that repeated doses of efgartigimod reduced IgG levels in healthy volunteers by 50%. Repeated dosing lowered IgG levels, on average by 75% in serum, which was an effect that was sustained for an 8-week period.⁶² Phase 2 trials are recruiting, with a projected primary completion in 2023.
 

INFECTION-INDUCED PERIPHERAL NEUROPATHY

Infections have been identified as a primary cause of peripheral neuropathy. Infection-induced peripheral neuropathy has been associated with Lyme disease, Epstein-Barr and human immunodeficiency virus (HIV) infection, shingles, hepatitis B and C, diphtheria, leprosy, and rabies.⁶³ Extensive research on peripheral neuropathy has not been completed for most of the diseases, highlighting an unmet need for patients who experience this sequela of infection.

HIV is a well-documented viral cause of peripheral neuropathy. The most common symptom is distal sensory polyneuropathy, which affects more than 50% of patients with HIV.⁶⁴ The incidence of distal sensory polyneuropathy in HIV has been correlated with the use of antiretroviral therapy – specifically, tenofovir disoproxil fumarate – and with certain proteins secreted by the virus.⁶⁵ Symptoms include loss of sensory properties, neuropathic pain, and allodynia.⁶⁶

Diagnostic tools and strategies

Nerve conduction studies have primarily been used to diagnose HIV-induced peripheral neuropathy, as well as electrophysiological testing and noninvasive CCM. These assays can detect changes or abnormalities in large- and small-fiber nerves in HIV infection patients.⁶⁶

Therapeutic options

Studies in mouse models have illustrated how the Tat protein correlates with induction of motor and sensory distal symmetric polyneuropathy. Expression of Tat can lead to mitochondrial disruption, resulting in degeneration of sensory dorsal root ganglia and subsequent neuropathic pain.⁶⁷

Pirenzepine. Studies on mice have identified a potential treatment for HIV infection-induced peripheral neuropathy with pirenzepine, targeting the muscarinic subtype-1 receptor. Pirenzepine activates a molecular pathway that promotes neurite growth and mitochondrial function. Researchers found that, following treatment with pirenzepine (n = 6), there was marked reduction in mitochondrial degeneration and HIV-induced distal sensory neuropathy.⁶⁶ This outcome was due to the ability of pirenzepine to block the effects of Tat protein expression, leading to reversal of its neurodegenerative effects.

Exercise combined with analgesics has also been identified as a potential treatment for alleviating distal sensory polyneuropathy in HIV infection–induced peripheral neuropathy. In a 12-week study, researchers instructed subjects who were receiving a combination of HIV treatments, including tenofovir, lamivudine, and efavirenz, to perform aerobic and resistance exercises. This regimen was intended to improve peripheral nerve-conduction velocity and increase the density of nerve fibers and neurogenic branching.

The study identified baseline pain scores and divided participants into three groups: aerobic exercise (n = 45), resistance exercise (n = 44), and controls (n = 47), for whom the average level of pain was 2 on an ascending scale of 1 to 10. There was significant reduction in pain score in the experimental groups by the end of the study, as well as an increased sensory profile.⁶⁴ This study has elucidated a pain management therapy for HIV-induced peripheral neuropathy that can prove beneficial for patients.
 

CRYPTOGENIC SENSORY POLYNEUROPATHY

Also known as idiopathic neuropathy or small-fiber sensory peripheral neuropathy, cryptogenic sensory polyneuropathy (CSPN) affects one-third of patients with peripheral neuropathy, in whom (despite extensive testing) no known cause of their condition is revealed.

Diagnostic tools and strategies

Applicable clinical and laboratory tests of any potential known underlying causes of neuropathy, including diabetes, hereditary disorders, and autoimmune disease, must be performed to rule out those causes and suggest an idiopathic cause.⁶⁸

Therapeutic options

There are no FDA-approved treatments for CSPN, as most treatments are geared toward neuropathic pain management, rehabilitation, and supportive care.⁶⁸ Due to a lack of research and data regarding these types of peripheral neuropathies, various studies suggest different first-line therapies. For example, anticonvulsants (pregabalin, gabapentin), antidepressants (duloxetine), and opioid-like compounds (tramadol) are all threapy options to treat DPN.³

Adequate data are lacking to support the efficacy of immunosuppressive therapy in CSPN.

Summing up

The combination of an understanding of a widening range of underlying diseases, advancements in cancer therapies, and the rising prevalence of diabetes have all led to an increasing incidence of peripheral neuropathy. Coupled with the fact that one-third of patients with peripheral neuropathy experience idiopathic neuropathy, this indicates that extensive studies must be undertaken to identify mitigation and prevention strategies for peripheral neuropathy. To summarize the landscape of treatment for peripheral neuropathy:

Diabetic peripheral neuropathy. Treatment for DPN comprises three FDA-approved products: pregabalin, duloxetine, and a higher (8%)-strength capsaicin patch.³ Pain-management therapies also exist to reduce diabetes-induced neuropathic pain, including gabapentin, amitriptyline, and extended-release tapentadol.¹⁰

Chemotherapy-induced peripheral neuropathy has yet to be effectively treated in humans; however, many trials are being completed in animals with promising results. Treatment for CIPN has been identified using senolytic agents, such as navitoclax,²² and through inhibition of SASP by a variety of agents, including ARV825, tocilizumab, and adalimumab.^23-26

Oxaliplatin-induced peripheral neuropathy. Research has identified a potential preventive agent in duloxetine, with human trials already showing efficacy and safety.²⁹ Animal models have shown progress studying antioxidant agents, such as amifostine³¹ and calmangafodipir,³² which target ion channels. In a similar mechanism of action, riluzole has been observed to reduce motor and sensory deficits and depression resulting from treatment with oxaliplatin.

Vincristine-induced peripheral neuropathy. Progress has been seen in treating vincristine-induced peripheral neuropathy with pyridoxine and pyridostigmine, which have improved neuropathy scores in trial subjects;³⁷ more studies must be completed before these agents can be established as effective therapy.

Autoimmune PN. There are no FDA-approved drugs to mitigate the peripheral neuropathy induced by GBS and CIDP; however, studies are being conducted to resolve this impediment. Potential treatments, such as ANX005, a recombinant antibody, and eculizumab, a monoclonal antibody, have both shown efficacy in human trials and provide a potential path toward treatment against peripheral neuropathy caused by GBS.^47,50 CIDP is currently treated using prednisone, plasmapheresis, and IVIG.⁴⁰ Clinical trials are studying the efficacy of rituximab and efgartigimod for CIDP.^58-60

Infection-induced peripheral neuropathy. Although many infections can induce peripheral neuropathy, HIV is most well documented and therefore was singled out for discussion in this article. Pirenzepine has been shown to promote neurite growth and reduce mitochondrial degeneration – both of which factors are associated with reduction of neuropathic pain.⁶⁶ Exercise and analgesics have also been found to mitigate the effects of HIV-induced distal sensory neuropathy, with pain scores being reduced.⁶¹

Cryptogenic sensory polyneuropathy. Research has yet to identify a causative agent of, or subsequent potential therapy for, CSPN. Increased knowledge about this neuropathy will, it is hoped, bring patients closer to a cure – beyond current pain mitigation strategies with anticonvulsants, antidepressants, and opioid-like compounds.³
 

Ms. Lee is a first-year master of science candidate in applied life sciences, with an emphasis on infectious diseases, and Mr. Kosacki is a first-year master of science candidate in applied life sciences, with an emphasis on translational research, both at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Bhandari is professor of clinical sciences and Dr. Tran is professor of clinical sciences, Keck Graduate Institute School of Pharmacy and Health Sciences.

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Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.

The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.

“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
 

Long-term results do not weaken SPRINT

One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.

“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”

The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.

For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.

“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
 

In SPRINT, CVD mortality reduced 43%

In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).

In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.

The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.

This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
 

Factors driving rising BP are unclear

There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.

“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”

In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”

Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.

This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.

“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.

“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.

The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.

Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.

The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.

The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.

“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
 

Long-term results do not weaken SPRINT

One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.

“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”

The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.

For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.

“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
 

In SPRINT, CVD mortality reduced 43%

In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).

In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.

The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.

This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
 

Factors driving rising BP are unclear

There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.

“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”

In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”

Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.

This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.

“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.

“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.

The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.

Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.

The substantial reductions in cardiovascular disease (CVD) and all-cause mortality achieved with intensive blood pressure lowering in the landmark SPRINT trial were not sustained in a newly released long-term follow-up.

The loss of the mortality benefits corresponded with a steady climb in the average systolic blood pressures (SBP) in the intensive treatment group after the trial ended. The long-term benefit serves as a call to develop better strategies for sustained SBP control.

“We were disappointed but not surprised that the blood pressure levels in the intensive goal group were not sustained,” acknowledged William C. Cushman, MD, Medical Director, department of preventive medicine, University of Tennessee Health Science Center, Memphis. “There are many trials showing no residual or legacy effect once the intervention is stopped.”
 

Long-term results do not weaken SPRINT

One of the coinvestigators of this most recent analysis published in JAMA Cardiology and a member of the SPRINT writing committee at the time of its 2015 publication in the New England Journal of Medicine, Dr. Cushman pointed out that the long-term results do not weaken the main trial result. Long-term adherence was not part of the trial design.

“After the trial, we were no longer treating these participants, so it was up to them and their primary care providers to decide on blood pressure goals,” he noted in an interview. Based on the trajectory of benefit when the study was stopped, “it is possible longer intensive treatment may lead to more benefit and some long-term residual benefits.”

The senior author of this most recent analysis, Nicholas M. Pajewski, PhD, associate professor of biostatistics and data science, Wake Forest University, Winston-Salem, N.C., generally agreed. However, he pointed out that the most recent data do not rule out meaningful benefit after the study ended.

For one reason, the loss of the SBP advantage was gradual so that median SBP levels of the two groups did not meet for nearly 3 years. This likely explains why there was still an attenuation of CVD mortality for several years after the all-cause mortality benefit was lost, according to Dr. Pajewski.

“It is important to mention that we were not able to assess nonfatal cardiovascular events, so while the two groups do eventually come together, if one thinks about the distinction of healthspan versus lifespan, there was probably residual benefit in terms of delaying CVD morbidity and mortality,” Dr. Pajewski said.
 

In SPRINT, CVD mortality reduced 43%

In the 9,631-patient SPRINT trial, the intensive treatment group achieved a mean SBP of 121.4 mm Hg versus 136.2 mm Hg in the standard treatment group at the end of 1 year. The trial was stopped early after 3.26 years because of strength of the benefit in the intensive treatment arm. At that time, the reductions by hazard ratio were 25% (HR, 0.75; P < .001) for a composite major adverse cardiovascular event (MACE) endpoint, 43% for CVD mortality (P = .005), and 27% for all-cause mortality (P = .003).

In the new observational follow-up, mortality data were drawn from the National Death Index, and change in SBP from electronic health records in a subset of 2,944 SPRINT trial participants. Data were available and analyzed through 2020.

The newly published long-term observational analysis showed that the median SBP in the intensive treatment arm was already climbing by the end of the end of the trial. It reached 132.8 mm Hg at 5 years after randomization and then 140.4 mm Hg by 10 years.

This latter figure was essentially equivalent to the SBP among those who were initially randomized to the standard treatment arm.
 

Factors driving rising BP are unclear

There is limited information on what medications were taken by either group following the end of the trial, so the reason for the regression in the intensive treatment arm after leaving the trial is unknown. The authors speculated that this might have been due to therapeutic inertia among treating physicians, poor adherence among patients, the difficulty of keeping blood pressures low in patients with advancing pathology, or some combination of these.

“Perhaps the most important reason was that providers and patients were not aiming for the lower goals since guidelines did not recommend these targets until 2017,” Dr. Cushman pointed out. He noted that Healthcare Effectiveness Data and Information Set (HEDIS) “has still not adopted a performance measure goal of less than 140 mm Hg.”

In an accompanying editorial, the authors focused on what these data mean for population-based strategies to achieve sustained control of one of the most important risk factors for cardiovascular events. Led by Daniel W. Jones, MD, director of clinical and population science, University of Mississippi, Jackson, the authors of the editorial wrote that these data emphasized “the challenge of achieving sustained intensive BP reductions in the real-world setting.”

Basically, the editorial concluded that current approaches to achieving meaningful and sustained blood pressure control are not working.

This study “should be a wakeup call, but other previously published good data have also been ignored,” said Dr. Jones in an interview. Despite the compelling benefit from intensive blood pressure control the SPRINT trial, the observational follow-up emphasizes the difficulty of maintaining the rigorous reductions in blood pressure needed for sustained protection.

“Systemic change is necessary,” said Dr. Jones, reprising the major thrust of the editorial he wrote with Donald Clark III, MD, and Michael E. Hall, MD, who are both colleagues at the University of Mississippi.

“My view is that health care providers should be held responsible for motivating better compliance of their patients, just as a teacher is accountable for the outcomes of their students,” he said.

The solutions are not likely to be simple. Dr. Jones called for multiple strategies, such as employing telehealth and community health workers to monitor and reinforce blood pressure control, but he said that these and other data have convinced him that “simply trying harder at what we currently do” is not enough.

Dr. Pajewski and Dr. Jones report no potential conflicts of interest. Dr. Cushman reports a financial relationship with ReCor.

A “high-intensity-care” strategy based on early and rapid uptitration of guideline-directed meds improves postdischarge clinical outcomes for patients hospitalized with decompensated heart failure (HF), suggest topline results from a randomized trial.

The STRONG-HF study was halted early on recommendation from its data safety monitoring board after an interim analysis suggested the high-intensity-care strategy significantly cut risk of death or HF readmission, compared with a standard-of-care approach.

The trial termination was announced  in a press release from one of its sponsors, The Heart Initiative, a nonprofit organization. STRONG-HF was also supported by Roche Diagnostics.

The early termination was based on interim data from the approximately 1,000 patients, out of an estimated planned enrollment of 1,800, who had been followed for at least 90 days. The study’s actual primary endpoint had been defined by death or HF readmission at 6 months.

The announcement did not include outcomes data or P values, or any other indication of the magnitude of benefit from the high-intensity-care approach.

Patients in STRONG-HF who had been assigned to a high-intensity-care strategy had been started in-hospital on a beta blocker, a renin-angiotensin system inhibitor (RASi), and a mineralocorticoid receptor blocker (MRA) with dosages uptitrated at least halfway by the time of discharge.

The meds were uptitrated fully within 2 weeks of discharge guided by clinical and biomarker assessments, especially natriuretic peptides, at frequent postdischarge visits, the press release states.

Patients conducted “safety visits 1 week after any uptitration and follow-up visits at 6 weeks and 3 months,” the announcement notes. “At each visit, patients were assessed by physical examination for congestion and blood tests, including NT-proBNP measurements.”

The “full STRONG-HF trial results” are scheduled for presentation at the American Heart Association annual scientific sessions, the announcement states.

STRONG-HF is sponsored by The Heart Initiative and Roche Diagnostics.

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

A “high-intensity-care” strategy based on early and rapid uptitration of guideline-directed meds improves postdischarge clinical outcomes for patients hospitalized with decompensated heart failure (HF), suggest topline results from a randomized trial.

The STRONG-HF study was halted early on recommendation from its data safety monitoring board after an interim analysis suggested the high-intensity-care strategy significantly cut risk of death or HF readmission, compared with a standard-of-care approach.

The trial termination was announced  in a press release from one of its sponsors, The Heart Initiative, a nonprofit organization. STRONG-HF was also supported by Roche Diagnostics.

The early termination was based on interim data from the approximately 1,000 patients, out of an estimated planned enrollment of 1,800, who had been followed for at least 90 days. The study’s actual primary endpoint had been defined by death or HF readmission at 6 months.

The announcement did not include outcomes data or P values, or any other indication of the magnitude of benefit from the high-intensity-care approach.

Patients in STRONG-HF who had been assigned to a high-intensity-care strategy had been started in-hospital on a beta blocker, a renin-angiotensin system inhibitor (RASi), and a mineralocorticoid receptor blocker (MRA) with dosages uptitrated at least halfway by the time of discharge.

The meds were uptitrated fully within 2 weeks of discharge guided by clinical and biomarker assessments, especially natriuretic peptides, at frequent postdischarge visits, the press release states.

Patients conducted “safety visits 1 week after any uptitration and follow-up visits at 6 weeks and 3 months,” the announcement notes. “At each visit, patients were assessed by physical examination for congestion and blood tests, including NT-proBNP measurements.”

The “full STRONG-HF trial results” are scheduled for presentation at the American Heart Association annual scientific sessions, the announcement states.

STRONG-HF is sponsored by The Heart Initiative and Roche Diagnostics.

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

A “high-intensity-care” strategy based on early and rapid uptitration of guideline-directed meds improves postdischarge clinical outcomes for patients hospitalized with decompensated heart failure (HF), suggest topline results from a randomized trial.

The STRONG-HF study was halted early on recommendation from its data safety monitoring board after an interim analysis suggested the high-intensity-care strategy significantly cut risk of death or HF readmission, compared with a standard-of-care approach.

The trial termination was announced  in a press release from one of its sponsors, The Heart Initiative, a nonprofit organization. STRONG-HF was also supported by Roche Diagnostics.

The early termination was based on interim data from the approximately 1,000 patients, out of an estimated planned enrollment of 1,800, who had been followed for at least 90 days. The study’s actual primary endpoint had been defined by death or HF readmission at 6 months.

The announcement did not include outcomes data or P values, or any other indication of the magnitude of benefit from the high-intensity-care approach.

Patients in STRONG-HF who had been assigned to a high-intensity-care strategy had been started in-hospital on a beta blocker, a renin-angiotensin system inhibitor (RASi), and a mineralocorticoid receptor blocker (MRA) with dosages uptitrated at least halfway by the time of discharge.

The meds were uptitrated fully within 2 weeks of discharge guided by clinical and biomarker assessments, especially natriuretic peptides, at frequent postdischarge visits, the press release states.

Patients conducted “safety visits 1 week after any uptitration and follow-up visits at 6 weeks and 3 months,” the announcement notes. “At each visit, patients were assessed by physical examination for congestion and blood tests, including NT-proBNP measurements.”

The “full STRONG-HF trial results” are scheduled for presentation at the American Heart Association annual scientific sessions, the announcement states.

STRONG-HF is sponsored by The Heart Initiative and Roche Diagnostics.

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

While rainbow-colored flags may wave proudly from hotel balconies and sports arenas, LGBTQ+ patients might still feel some discrimination in the medical space, according to a Center for American Progress survey.

“Despite health care being considered a basic human right by the World Health Organization, it’s common for LGBTQ+ folks to face difficulties not only when trying to access care but also within the walls of the doctor’s office or hospital,” says Samantha Estevez, MD, a reproductive endocrinology and infertility fellow in New York.

In Medscape’s Physicians’ Views on LGBTQ+ Rights Issues Report 2022: Strong Emotions, Contrary Opinions, physicians were asked whether they see disparities in the care LGBTQ+ patients receive in comparison with the care that non-LGBTQ+ patients receive. About 35% of physicians said LGBTQ+ patients receive a different level of care; 52% of respondents younger than 45 said so.

It’s an issue unlikely to be resolved without the medical community’s awareness. With insights from four LGBTQ+ clinicians, here are several steps physicians can take to close the disparity gap.
 

Update intake forms

Many patient medical forms are populated with checkboxes. These forms may make it easier for patients to share their medical information and for practices to collect data. But unfortunately, they don’t allow for patients to fill in contextual information.

“It’s extremely important for health care professionals to understand the people they are serving,” says Nicholas Grant, PhD, ABPP, president of GLMA: Health Professionals Advancing LGBTQ+ Equality. Dr. Grant is a board-certified clinical psychologist in Hawaii. “The more accurate we are with our information gathering and paperwork, the more accurate we will be at serving our LGBTQ+ communities.”

Dr. Grant recommends asking open-ended questions, such as the following:

• What is your gender identity?
• What was your assigned sex at birth?
• What pronouns do you prefer?
• What gender(s) are your sexual partners?

However, Frances Grimstad, MD, a Boston-based ob/gyn and GLMA board member, adds this advice: Before revising intake forms, consider their purpose.

“As an ob/gyn, information about a patient’s sexual orientation and their sexual activity is beneficial for my care,” says Dr. Grimstad. “But that information may not be relevant for a physical therapy clinic where most patients are coming in with knee injuries. So, you shouldn’t just place items on your intake forms by default. Instead, clinicians should consider what is relevant to the encounter you’re having and how you are going to use the information.”
 

Change signage

Take stock of posters and brochures in the office and signs outside restrooms. If they communicate traditional gender roles, then it may be time for a change.

“It’s important to ensure representation of all types of people and families in your office,” says Chase Anderson, MD, an assistant professor of child and adolescent psychiatry in San Francisco.

Hang posters with images of diverse families. Display brochures that address LGBTQ+ health concerns when warranted. And for restrooms, replace traditional binary images with gender-neutral ones. You can also add signage about each bathroom’s purpose, suggests Dr. Grimstad.

“Let’s not just de-gender bathrooms,” she says. “Let’s hang signs that tell if the bathroom has multiple stalls, urinals, or handicap access. Let signage focus on the functions of each bathroom, not gender.”
 

Ask for feedback

Feedback forms give LBGTQ+ patients a platform to share concerns. For example, consider an email with a linked document that all patients can fill out anonymously. Ask questions such as the following:

• Did you feel affirmed during your appointment? If so, how? If not, how can we improve?
• Did we use the proper pronouns?
• Did signage make you feel like you were in a safe space? What didn’t make you feel safe?

Set up a system with team members to process feedback and implement changes.

Also, if you have a large-scale practice, consider forming an LGBTQ+ community advisory board. “They can offer feedback about your practice’s clinical structure,” Dr. Grimstad tells Medscape.
 

Hire diverse employees

Building a diverse and inclusive workforce is critical to serving the LBGTQ+ community. Team members should reflect your patient population.

“Diversity isn’t a monolith,” says Dr. Grimstad. “It isn’t just racial diversity, or sexual or gender diversity. Even in a town which appears homogeneous in one area of diversity, such as a majority White town, it’s important to remember all the other facets of diversity that exist, such as gender, sexual orientation, cultural diversity.”

A diverse team may offer a surprising boost to your practice. According to a study published in the Journal of the National Medical Association, patient outcomes improve when a more diverse team provides care. In fact, diverse teams fare better in innovation, communication, risk assessment, and financial performance.

Dr. Anderson also recommends allowing team members “to be themselves.” For example, let employees wear their hair in whatever way they prefer or display their tattoos.

“This signals to patients that if staff members can be themselves here, patients can be themselves here, too,” says Dr. Anderson.
 

Provide training

Medical staff may sometimes feel uncomfortable serving LBGTQ+ patients because of their own biases, attitudes, or lack of knowledge about the community. Regular training can ease their discomfort.

“Make sure all health professionals are trained and educated on the needs of LGBTQ+ patients,” says Dr. Grant. “Understanding their health needs is the provider’s responsibility.”

For basic information, Dr. Anderson recommends visiting The Trevor Project, an organization that serves LGBTQ+ youth. “They’re really good at keeping up with changing verbiage and trends,” says Dr. Anderson.

To strengthen community connections, Dr. Grimstad recommends using trainers from your local area if possible. Do a Google search to find an LGBTQ+ center nearby or in the closest major city. Invite them to staff meetings or ask them to organize a workshop.

By implementing these strategies, you can start building a bridge between your practice and the LGBTQ+ community and provide better care for them as patients.

“Whether it’s knowing about PrEP ... or ensuring staff members are trained in caring for patients with any general or sexual identity, we as doctors and medical professionals must continue to move forward and serve our LGBTQ+ patients in big and small ways,” says Dr. Estevez.

For in-depth training, check the following organizations:

National LGBTQIA+ Health Education Center at the Fenway Institute provides educational programs and resources to health care organizations.

GLMA has a top 10 health issues webpage that doctors can use to educate themselves and staff members on the LGBTQ+ community’s most urgent health needs.

Alliance for Full Acceptance offers LGBTQ cultural competency training, including a 1-hour awareness class and a 3-hour inclusivity workshop for clinicians.

The Substance Abuse and Mental Health Services Administration has compiled a list of training curricula for behavioral health counselors and primary care providers.

UCSF’s Lesbian, Gay, Bisexual, and Transgender Resource Center has a list of training and educational materials for medical professionals.

Equality California Institute offers both in-person and virtual training covering basic terminology, data on LGBTQ+ health issues, and how to create an inclusive environment.

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

While rainbow-colored flags may wave proudly from hotel balconies and sports arenas, LGBTQ+ patients might still feel some discrimination in the medical space, according to a Center for American Progress survey.

“Despite health care being considered a basic human right by the World Health Organization, it’s common for LGBTQ+ folks to face difficulties not only when trying to access care but also within the walls of the doctor’s office or hospital,” says Samantha Estevez, MD, a reproductive endocrinology and infertility fellow in New York.

In Medscape’s Physicians’ Views on LGBTQ+ Rights Issues Report 2022: Strong Emotions, Contrary Opinions, physicians were asked whether they see disparities in the care LGBTQ+ patients receive in comparison with the care that non-LGBTQ+ patients receive. About 35% of physicians said LGBTQ+ patients receive a different level of care; 52% of respondents younger than 45 said so.

It’s an issue unlikely to be resolved without the medical community’s awareness. With insights from four LGBTQ+ clinicians, here are several steps physicians can take to close the disparity gap.
 

Update intake forms

Many patient medical forms are populated with checkboxes. These forms may make it easier for patients to share their medical information and for practices to collect data. But unfortunately, they don’t allow for patients to fill in contextual information.

“It’s extremely important for health care professionals to understand the people they are serving,” says Nicholas Grant, PhD, ABPP, president of GLMA: Health Professionals Advancing LGBTQ+ Equality. Dr. Grant is a board-certified clinical psychologist in Hawaii. “The more accurate we are with our information gathering and paperwork, the more accurate we will be at serving our LGBTQ+ communities.”

Dr. Grant recommends asking open-ended questions, such as the following:

• What is your gender identity?
• What was your assigned sex at birth?
• What pronouns do you prefer?
• What gender(s) are your sexual partners?

However, Frances Grimstad, MD, a Boston-based ob/gyn and GLMA board member, adds this advice: Before revising intake forms, consider their purpose.

“As an ob/gyn, information about a patient’s sexual orientation and their sexual activity is beneficial for my care,” says Dr. Grimstad. “But that information may not be relevant for a physical therapy clinic where most patients are coming in with knee injuries. So, you shouldn’t just place items on your intake forms by default. Instead, clinicians should consider what is relevant to the encounter you’re having and how you are going to use the information.”
 

Change signage

Take stock of posters and brochures in the office and signs outside restrooms. If they communicate traditional gender roles, then it may be time for a change.

“It’s important to ensure representation of all types of people and families in your office,” says Chase Anderson, MD, an assistant professor of child and adolescent psychiatry in San Francisco.

Hang posters with images of diverse families. Display brochures that address LGBTQ+ health concerns when warranted. And for restrooms, replace traditional binary images with gender-neutral ones. You can also add signage about each bathroom’s purpose, suggests Dr. Grimstad.

“Let’s not just de-gender bathrooms,” she says. “Let’s hang signs that tell if the bathroom has multiple stalls, urinals, or handicap access. Let signage focus on the functions of each bathroom, not gender.”
 

Ask for feedback

Feedback forms give LBGTQ+ patients a platform to share concerns. For example, consider an email with a linked document that all patients can fill out anonymously. Ask questions such as the following:

• Did you feel affirmed during your appointment? If so, how? If not, how can we improve?
• Did we use the proper pronouns?
• Did signage make you feel like you were in a safe space? What didn’t make you feel safe?

Set up a system with team members to process feedback and implement changes.

Also, if you have a large-scale practice, consider forming an LGBTQ+ community advisory board. “They can offer feedback about your practice’s clinical structure,” Dr. Grimstad tells Medscape.
 

Hire diverse employees

Building a diverse and inclusive workforce is critical to serving the LBGTQ+ community. Team members should reflect your patient population.

“Diversity isn’t a monolith,” says Dr. Grimstad. “It isn’t just racial diversity, or sexual or gender diversity. Even in a town which appears homogeneous in one area of diversity, such as a majority White town, it’s important to remember all the other facets of diversity that exist, such as gender, sexual orientation, cultural diversity.”

A diverse team may offer a surprising boost to your practice. According to a study published in the Journal of the National Medical Association, patient outcomes improve when a more diverse team provides care. In fact, diverse teams fare better in innovation, communication, risk assessment, and financial performance.

Dr. Anderson also recommends allowing team members “to be themselves.” For example, let employees wear their hair in whatever way they prefer or display their tattoos.

“This signals to patients that if staff members can be themselves here, patients can be themselves here, too,” says Dr. Anderson.
 

Provide training

Medical staff may sometimes feel uncomfortable serving LBGTQ+ patients because of their own biases, attitudes, or lack of knowledge about the community. Regular training can ease their discomfort.

“Make sure all health professionals are trained and educated on the needs of LGBTQ+ patients,” says Dr. Grant. “Understanding their health needs is the provider’s responsibility.”

For basic information, Dr. Anderson recommends visiting The Trevor Project, an organization that serves LGBTQ+ youth. “They’re really good at keeping up with changing verbiage and trends,” says Dr. Anderson.

To strengthen community connections, Dr. Grimstad recommends using trainers from your local area if possible. Do a Google search to find an LGBTQ+ center nearby or in the closest major city. Invite them to staff meetings or ask them to organize a workshop.

By implementing these strategies, you can start building a bridge between your practice and the LGBTQ+ community and provide better care for them as patients.

“Whether it’s knowing about PrEP ... or ensuring staff members are trained in caring for patients with any general or sexual identity, we as doctors and medical professionals must continue to move forward and serve our LGBTQ+ patients in big and small ways,” says Dr. Estevez.

For in-depth training, check the following organizations:

National LGBTQIA+ Health Education Center at the Fenway Institute provides educational programs and resources to health care organizations.

GLMA has a top 10 health issues webpage that doctors can use to educate themselves and staff members on the LGBTQ+ community’s most urgent health needs.

Alliance for Full Acceptance offers LGBTQ cultural competency training, including a 1-hour awareness class and a 3-hour inclusivity workshop for clinicians.

The Substance Abuse and Mental Health Services Administration has compiled a list of training curricula for behavioral health counselors and primary care providers.

UCSF’s Lesbian, Gay, Bisexual, and Transgender Resource Center has a list of training and educational materials for medical professionals.

Equality California Institute offers both in-person and virtual training covering basic terminology, data on LGBTQ+ health issues, and how to create an inclusive environment.

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

While rainbow-colored flags may wave proudly from hotel balconies and sports arenas, LGBTQ+ patients might still feel some discrimination in the medical space, according to a Center for American Progress survey.

“Despite health care being considered a basic human right by the World Health Organization, it’s common for LGBTQ+ folks to face difficulties not only when trying to access care but also within the walls of the doctor’s office or hospital,” says Samantha Estevez, MD, a reproductive endocrinology and infertility fellow in New York.

In Medscape’s Physicians’ Views on LGBTQ+ Rights Issues Report 2022: Strong Emotions, Contrary Opinions, physicians were asked whether they see disparities in the care LGBTQ+ patients receive in comparison with the care that non-LGBTQ+ patients receive. About 35% of physicians said LGBTQ+ patients receive a different level of care; 52% of respondents younger than 45 said so.

It’s an issue unlikely to be resolved without the medical community’s awareness. With insights from four LGBTQ+ clinicians, here are several steps physicians can take to close the disparity gap.
 

Update intake forms

Many patient medical forms are populated with checkboxes. These forms may make it easier for patients to share their medical information and for practices to collect data. But unfortunately, they don’t allow for patients to fill in contextual information.

“It’s extremely important for health care professionals to understand the people they are serving,” says Nicholas Grant, PhD, ABPP, president of GLMA: Health Professionals Advancing LGBTQ+ Equality. Dr. Grant is a board-certified clinical psychologist in Hawaii. “The more accurate we are with our information gathering and paperwork, the more accurate we will be at serving our LGBTQ+ communities.”

Dr. Grant recommends asking open-ended questions, such as the following:

• What is your gender identity?
• What was your assigned sex at birth?
• What pronouns do you prefer?
• What gender(s) are your sexual partners?

However, Frances Grimstad, MD, a Boston-based ob/gyn and GLMA board member, adds this advice: Before revising intake forms, consider their purpose.

“As an ob/gyn, information about a patient’s sexual orientation and their sexual activity is beneficial for my care,” says Dr. Grimstad. “But that information may not be relevant for a physical therapy clinic where most patients are coming in with knee injuries. So, you shouldn’t just place items on your intake forms by default. Instead, clinicians should consider what is relevant to the encounter you’re having and how you are going to use the information.”
 

Change signage

Take stock of posters and brochures in the office and signs outside restrooms. If they communicate traditional gender roles, then it may be time for a change.

“It’s important to ensure representation of all types of people and families in your office,” says Chase Anderson, MD, an assistant professor of child and adolescent psychiatry in San Francisco.

Hang posters with images of diverse families. Display brochures that address LGBTQ+ health concerns when warranted. And for restrooms, replace traditional binary images with gender-neutral ones. You can also add signage about each bathroom’s purpose, suggests Dr. Grimstad.

“Let’s not just de-gender bathrooms,” she says. “Let’s hang signs that tell if the bathroom has multiple stalls, urinals, or handicap access. Let signage focus on the functions of each bathroom, not gender.”
 

Ask for feedback

Feedback forms give LBGTQ+ patients a platform to share concerns. For example, consider an email with a linked document that all patients can fill out anonymously. Ask questions such as the following:

• Did you feel affirmed during your appointment? If so, how? If not, how can we improve?
• Did we use the proper pronouns?
• Did signage make you feel like you were in a safe space? What didn’t make you feel safe?

Set up a system with team members to process feedback and implement changes.

Also, if you have a large-scale practice, consider forming an LGBTQ+ community advisory board. “They can offer feedback about your practice’s clinical structure,” Dr. Grimstad tells Medscape.
 

Hire diverse employees

Building a diverse and inclusive workforce is critical to serving the LBGTQ+ community. Team members should reflect your patient population.

“Diversity isn’t a monolith,” says Dr. Grimstad. “It isn’t just racial diversity, or sexual or gender diversity. Even in a town which appears homogeneous in one area of diversity, such as a majority White town, it’s important to remember all the other facets of diversity that exist, such as gender, sexual orientation, cultural diversity.”

A diverse team may offer a surprising boost to your practice. According to a study published in the Journal of the National Medical Association, patient outcomes improve when a more diverse team provides care. In fact, diverse teams fare better in innovation, communication, risk assessment, and financial performance.

Dr. Anderson also recommends allowing team members “to be themselves.” For example, let employees wear their hair in whatever way they prefer or display their tattoos.

“This signals to patients that if staff members can be themselves here, patients can be themselves here, too,” says Dr. Anderson.
 

Provide training

Medical staff may sometimes feel uncomfortable serving LBGTQ+ patients because of their own biases, attitudes, or lack of knowledge about the community. Regular training can ease their discomfort.

“Make sure all health professionals are trained and educated on the needs of LGBTQ+ patients,” says Dr. Grant. “Understanding their health needs is the provider’s responsibility.”

For basic information, Dr. Anderson recommends visiting The Trevor Project, an organization that serves LGBTQ+ youth. “They’re really good at keeping up with changing verbiage and trends,” says Dr. Anderson.

To strengthen community connections, Dr. Grimstad recommends using trainers from your local area if possible. Do a Google search to find an LGBTQ+ center nearby or in the closest major city. Invite them to staff meetings or ask them to organize a workshop.

By implementing these strategies, you can start building a bridge between your practice and the LGBTQ+ community and provide better care for them as patients.

“Whether it’s knowing about PrEP ... or ensuring staff members are trained in caring for patients with any general or sexual identity, we as doctors and medical professionals must continue to move forward and serve our LGBTQ+ patients in big and small ways,” says Dr. Estevez.

For in-depth training, check the following organizations:

National LGBTQIA+ Health Education Center at the Fenway Institute provides educational programs and resources to health care organizations.

GLMA has a top 10 health issues webpage that doctors can use to educate themselves and staff members on the LGBTQ+ community’s most urgent health needs.

Alliance for Full Acceptance offers LGBTQ cultural competency training, including a 1-hour awareness class and a 3-hour inclusivity workshop for clinicians.

The Substance Abuse and Mental Health Services Administration has compiled a list of training curricula for behavioral health counselors and primary care providers.

UCSF’s Lesbian, Gay, Bisexual, and Transgender Resource Center has a list of training and educational materials for medical professionals.

Equality California Institute offers both in-person and virtual training covering basic terminology, data on LGBTQ+ health issues, and how to create an inclusive environment.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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