Like most of you, I had always thought I was invincible and would live forever, but the kids had gotten out of the house (at least for now) and Medicare and Social Security were looming, so it was time to redo the will and think about estate planning. And then I met Zeus’ thunderbolt!

For the last couple of years, I had been getting dizzy when pulling weeds, and 2 months ago, felt like I had been hit by a truck. One hour of yard work and I had to lie in the grass and pant like a dog, or pass out. My internist and I both had COVID-19 on the brain, but all tests were negative; however, the chest x-ray showed atelectasis. What? So I had good and bad days, and noticed that my pulse was 150 when I climbed two flights of stairs. Finally, my wife insisted I get an EKG, which showed atrial flutter/fibrillation and a new right-bundle branch block.

I was ruled out for infarction or a pulmonary embolism and after 6 days on heparin, confirmation that I had clean coronaries (yes, statins should be in the water), and no atrial clot, I got to meet Zeus. They all say, “oh you won’t remember it” or “it won’t hurt.” But let me tell you, the closest thing I recall to having 200 joules shot through you from front to back is being kicked across the milk barn by an angry cow. I hollered, I don’t recall exactly what, but hey, Mr. Sinus Rhythm, my new long-lost friend was back.

I feel great again and have since had an ablation (no big deal, but they poke a hole in your atrium!) and have been fitted with a sleep snorkel, and can once again work all day in the yard.

Personally, meeting Zeus has changed my perspective on life, retirement and estate planning, and personal perspective on work. I highly recommend the book, “Wealth Planning for the Modern Physician: Residency to Retirement.” It is a pretty easy read and an eye opener. If taxes increase, and I don’t see how they can’t considering pandemic expenses, careful planning will be more important than ever.

After careful consideration, we are going to give most of our money to charities (institutions my wife and I we figure we owe a debt), such as colleges and residency programs. I am also going to make an active effort to cut back on work I don’t enjoy (goodbye endless committee meetings!), though I do enjoy my patients very much and will continue to practice. I relish the conversation and interaction, but hate the human relations part of practice management. I’m not much of a golfer, but enjoy gardening, writing, and public speaking. I love my children a lot, but I am still waiting for them to make their personal orbit around the universe so they can come home and be close again. We may also build a house in Florida with a terrace where we can garden without the deer’s help.

There was a recent survey that showed a lot of physicians are reconsidering their practice environments amid COVID-19 and as many as 5% considering retirement. This pandemic is going to put a lot of pressure on smaller practices to close or consolidate, which I think is a bad thing for physicians and patients. It is also the wrong time for physicians to be retiring when 10,000 baby boomers a day are turning 65, and some of them will need thunderbolts like me.

I also enjoy writing this column and sharing my life with you. It is an incredibly special thing to be able to openly share one’s loves, fears, and hopes with colleagues. So keep practicing, remember not all hoof beats are from COVID-19, try not to spoil the kids too much, keep one eye on the calendar, and beware Zeus’ thunderbolt!

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

Like most of you, I had always thought I was invincible and would live forever, but the kids had gotten out of the house (at least for now) and Medicare and Social Security were looming, so it was time to redo the will and think about estate planning. And then I met Zeus’ thunderbolt!

For the last couple of years, I had been getting dizzy when pulling weeds, and 2 months ago, felt like I had been hit by a truck. One hour of yard work and I had to lie in the grass and pant like a dog, or pass out. My internist and I both had COVID-19 on the brain, but all tests were negative; however, the chest x-ray showed atelectasis. What? So I had good and bad days, and noticed that my pulse was 150 when I climbed two flights of stairs. Finally, my wife insisted I get an EKG, which showed atrial flutter/fibrillation and a new right-bundle branch block.

I was ruled out for infarction or a pulmonary embolism and after 6 days on heparin, confirmation that I had clean coronaries (yes, statins should be in the water), and no atrial clot, I got to meet Zeus. They all say, “oh you won’t remember it” or “it won’t hurt.” But let me tell you, the closest thing I recall to having 200 joules shot through you from front to back is being kicked across the milk barn by an angry cow. I hollered, I don’t recall exactly what, but hey, Mr. Sinus Rhythm, my new long-lost friend was back.

I feel great again and have since had an ablation (no big deal, but they poke a hole in your atrium!) and have been fitted with a sleep snorkel, and can once again work all day in the yard.

Personally, meeting Zeus has changed my perspective on life, retirement and estate planning, and personal perspective on work. I highly recommend the book, “Wealth Planning for the Modern Physician: Residency to Retirement.” It is a pretty easy read and an eye opener. If taxes increase, and I don’t see how they can’t considering pandemic expenses, careful planning will be more important than ever.

After careful consideration, we are going to give most of our money to charities (institutions my wife and I we figure we owe a debt), such as colleges and residency programs. I am also going to make an active effort to cut back on work I don’t enjoy (goodbye endless committee meetings!), though I do enjoy my patients very much and will continue to practice. I relish the conversation and interaction, but hate the human relations part of practice management. I’m not much of a golfer, but enjoy gardening, writing, and public speaking. I love my children a lot, but I am still waiting for them to make their personal orbit around the universe so they can come home and be close again. We may also build a house in Florida with a terrace where we can garden without the deer’s help.

There was a recent survey that showed a lot of physicians are reconsidering their practice environments amid COVID-19 and as many as 5% considering retirement. This pandemic is going to put a lot of pressure on smaller practices to close or consolidate, which I think is a bad thing for physicians and patients. It is also the wrong time for physicians to be retiring when 10,000 baby boomers a day are turning 65, and some of them will need thunderbolts like me.

I also enjoy writing this column and sharing my life with you. It is an incredibly special thing to be able to openly share one’s loves, fears, and hopes with colleagues. So keep practicing, remember not all hoof beats are from COVID-19, try not to spoil the kids too much, keep one eye on the calendar, and beware Zeus’ thunderbolt!

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

Like most of you, I had always thought I was invincible and would live forever, but the kids had gotten out of the house (at least for now) and Medicare and Social Security were looming, so it was time to redo the will and think about estate planning. And then I met Zeus’ thunderbolt!

For the last couple of years, I had been getting dizzy when pulling weeds, and 2 months ago, felt like I had been hit by a truck. One hour of yard work and I had to lie in the grass and pant like a dog, or pass out. My internist and I both had COVID-19 on the brain, but all tests were negative; however, the chest x-ray showed atelectasis. What? So I had good and bad days, and noticed that my pulse was 150 when I climbed two flights of stairs. Finally, my wife insisted I get an EKG, which showed atrial flutter/fibrillation and a new right-bundle branch block.

I was ruled out for infarction or a pulmonary embolism and after 6 days on heparin, confirmation that I had clean coronaries (yes, statins should be in the water), and no atrial clot, I got to meet Zeus. They all say, “oh you won’t remember it” or “it won’t hurt.” But let me tell you, the closest thing I recall to having 200 joules shot through you from front to back is being kicked across the milk barn by an angry cow. I hollered, I don’t recall exactly what, but hey, Mr. Sinus Rhythm, my new long-lost friend was back.

I feel great again and have since had an ablation (no big deal, but they poke a hole in your atrium!) and have been fitted with a sleep snorkel, and can once again work all day in the yard.

Personally, meeting Zeus has changed my perspective on life, retirement and estate planning, and personal perspective on work. I highly recommend the book, “Wealth Planning for the Modern Physician: Residency to Retirement.” It is a pretty easy read and an eye opener. If taxes increase, and I don’t see how they can’t considering pandemic expenses, careful planning will be more important than ever.

After careful consideration, we are going to give most of our money to charities (institutions my wife and I we figure we owe a debt), such as colleges and residency programs. I am also going to make an active effort to cut back on work I don’t enjoy (goodbye endless committee meetings!), though I do enjoy my patients very much and will continue to practice. I relish the conversation and interaction, but hate the human relations part of practice management. I’m not much of a golfer, but enjoy gardening, writing, and public speaking. I love my children a lot, but I am still waiting for them to make their personal orbit around the universe so they can come home and be close again. We may also build a house in Florida with a terrace where we can garden without the deer’s help.

There was a recent survey that showed a lot of physicians are reconsidering their practice environments amid COVID-19 and as many as 5% considering retirement. This pandemic is going to put a lot of pressure on smaller practices to close or consolidate, which I think is a bad thing for physicians and patients. It is also the wrong time for physicians to be retiring when 10,000 baby boomers a day are turning 65, and some of them will need thunderbolts like me.

I also enjoy writing this column and sharing my life with you. It is an incredibly special thing to be able to openly share one’s loves, fears, and hopes with colleagues. So keep practicing, remember not all hoof beats are from COVID-19, try not to spoil the kids too much, keep one eye on the calendar, and beware Zeus’ thunderbolt!

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

As an ophthalmologist who’s been performing vision correction surgery in the San Francisco Bay Area for more than 20 years, I want to address a rising concern I’ve seen among parents I’ve recently treated who currently have kids at home attending virtual classroom instruction.

Shelyna Long/Getty Images

Many of these parents are asking me if excessive screen time can be harmful to their children’s developing vision, especially if they are potentially genetically predisposed to myopia – also known as nearsightedness. While the short answer is, yes it can, there are safety measures that parents can put in place to greatly reduce the risk of vision damage caused by eye fatigue caused by long-term screen exposure.

Eye fatigue, also called digital eye strain, is a physical eye discomfort that is caused by excessive screen use, and is a common condition in both children and adults.

Today, more than 40% of Americans are myopic, and that number is increasing at an alarming rate, especially among school-aged children. One in four parents have a child with myopia, and about three quarters of children with myopia were diagnosed between the ages of 3 and 12 years.

A recent ParentsTogether study found that a majority of parents surveyed said they are concerned about a massive spike in their children’s screen time during the coronavirus pandemic. And nearly half of respondents’ children (48%) are currently spending more than 6 hours per day online – a nearly 500% increase from before the crisis.

While glasses or contact lenses can correct a child’s vision, research in the journal Retina by the Ikuno Eye Center in Osaka, Japan, suggests that having severe myopia puts children at risk for a number of eye problems down the road, including retinal detachment, glaucoma, and macular degeneration. Research published in PLOS ONE found that working up close – such as reading or using a tablet – increased the odds of myopia. And in a report published in Ophthalmology, researchers studying myopia have estimated that, by 2050, about half the world’s population could be myopic.
 

Watch for warning signs

To determine if excessive screen time is affecting your child, there warning signs to watch out for including the following:

• Eye irritation.
• Watery eyes.
• Headaches.
• Intermittent blurry vision or double vision.
• Sore eyes.
• Difficulty concentrating.
• Sore neck, shoulders, and/or back.
• Increased sensitivity to light.
• Tiredness.
• Poor posture.

Use these approaches to reduce eye fatigue

To reduce eye fatigue associated with excessive screen exposure, parents should set limits on screen time if possible, and at minimum, schedule between 8 and 15 hours of outdoor activity per week. Screens should be at least 20 centimeters away from the child’s eyes, the child’s desk should be placed near a window, and she should be instructed to look outside every hour. Lastly, children should be kept in fully corrected glasses, not under corrected, and those glasses need to be worn full time.

As we plan the future of education in the age of COVID-19, I firmly believe that schools and policymakers must consider children’s vision needs while designing new initiatives. Schools, teachers, and parents must work together to incorporate eye health strategies that protect children as they learn online. By doing so, we can decrease the chance that a child’s vision becomes compromised from unwittingly staring into a screen for too many hours during the day.
 

Dr. Faktorovich is an ophthalmologist, founder of Pacific Vision Institute in San Francisco, California, and founder of the annual San Francisco Cornea, Cataract, and Refractive Surgery Symposium. She had no relevant financial disclosures. Email her at [email protected].

As an ophthalmologist who’s been performing vision correction surgery in the San Francisco Bay Area for more than 20 years, I want to address a rising concern I’ve seen among parents I’ve recently treated who currently have kids at home attending virtual classroom instruction.

Shelyna Long/Getty Images

Many of these parents are asking me if excessive screen time can be harmful to their children’s developing vision, especially if they are potentially genetically predisposed to myopia – also known as nearsightedness. While the short answer is, yes it can, there are safety measures that parents can put in place to greatly reduce the risk of vision damage caused by eye fatigue caused by long-term screen exposure.

Eye fatigue, also called digital eye strain, is a physical eye discomfort that is caused by excessive screen use, and is a common condition in both children and adults.

Today, more than 40% of Americans are myopic, and that number is increasing at an alarming rate, especially among school-aged children. One in four parents have a child with myopia, and about three quarters of children with myopia were diagnosed between the ages of 3 and 12 years.

A recent ParentsTogether study found that a majority of parents surveyed said they are concerned about a massive spike in their children’s screen time during the coronavirus pandemic. And nearly half of respondents’ children (48%) are currently spending more than 6 hours per day online – a nearly 500% increase from before the crisis.

While glasses or contact lenses can correct a child’s vision, research in the journal Retina by the Ikuno Eye Center in Osaka, Japan, suggests that having severe myopia puts children at risk for a number of eye problems down the road, including retinal detachment, glaucoma, and macular degeneration. Research published in PLOS ONE found that working up close – such as reading or using a tablet – increased the odds of myopia. And in a report published in Ophthalmology, researchers studying myopia have estimated that, by 2050, about half the world’s population could be myopic.
 

Watch for warning signs

To determine if excessive screen time is affecting your child, there warning signs to watch out for including the following:

• Eye irritation.
• Watery eyes.
• Headaches.
• Intermittent blurry vision or double vision.
• Sore eyes.
• Difficulty concentrating.
• Sore neck, shoulders, and/or back.
• Increased sensitivity to light.
• Tiredness.
• Poor posture.

Use these approaches to reduce eye fatigue

To reduce eye fatigue associated with excessive screen exposure, parents should set limits on screen time if possible, and at minimum, schedule between 8 and 15 hours of outdoor activity per week. Screens should be at least 20 centimeters away from the child’s eyes, the child’s desk should be placed near a window, and she should be instructed to look outside every hour. Lastly, children should be kept in fully corrected glasses, not under corrected, and those glasses need to be worn full time.

As we plan the future of education in the age of COVID-19, I firmly believe that schools and policymakers must consider children’s vision needs while designing new initiatives. Schools, teachers, and parents must work together to incorporate eye health strategies that protect children as they learn online. By doing so, we can decrease the chance that a child’s vision becomes compromised from unwittingly staring into a screen for too many hours during the day.
 

Dr. Faktorovich is an ophthalmologist, founder of Pacific Vision Institute in San Francisco, California, and founder of the annual San Francisco Cornea, Cataract, and Refractive Surgery Symposium. She had no relevant financial disclosures. Email her at [email protected].

As an ophthalmologist who’s been performing vision correction surgery in the San Francisco Bay Area for more than 20 years, I want to address a rising concern I’ve seen among parents I’ve recently treated who currently have kids at home attending virtual classroom instruction.

Shelyna Long/Getty Images

Many of these parents are asking me if excessive screen time can be harmful to their children’s developing vision, especially if they are potentially genetically predisposed to myopia – also known as nearsightedness. While the short answer is, yes it can, there are safety measures that parents can put in place to greatly reduce the risk of vision damage caused by eye fatigue caused by long-term screen exposure.

Eye fatigue, also called digital eye strain, is a physical eye discomfort that is caused by excessive screen use, and is a common condition in both children and adults.

Today, more than 40% of Americans are myopic, and that number is increasing at an alarming rate, especially among school-aged children. One in four parents have a child with myopia, and about three quarters of children with myopia were diagnosed between the ages of 3 and 12 years.

A recent ParentsTogether study found that a majority of parents surveyed said they are concerned about a massive spike in their children’s screen time during the coronavirus pandemic. And nearly half of respondents’ children (48%) are currently spending more than 6 hours per day online – a nearly 500% increase from before the crisis.

While glasses or contact lenses can correct a child’s vision, research in the journal Retina by the Ikuno Eye Center in Osaka, Japan, suggests that having severe myopia puts children at risk for a number of eye problems down the road, including retinal detachment, glaucoma, and macular degeneration. Research published in PLOS ONE found that working up close – such as reading or using a tablet – increased the odds of myopia. And in a report published in Ophthalmology, researchers studying myopia have estimated that, by 2050, about half the world’s population could be myopic.
 

Watch for warning signs

To determine if excessive screen time is affecting your child, there warning signs to watch out for including the following:

• Eye irritation.
• Watery eyes.
• Headaches.
• Intermittent blurry vision or double vision.
• Sore eyes.
• Difficulty concentrating.
• Sore neck, shoulders, and/or back.
• Increased sensitivity to light.
• Tiredness.
• Poor posture.

Use these approaches to reduce eye fatigue

To reduce eye fatigue associated with excessive screen exposure, parents should set limits on screen time if possible, and at minimum, schedule between 8 and 15 hours of outdoor activity per week. Screens should be at least 20 centimeters away from the child’s eyes, the child’s desk should be placed near a window, and she should be instructed to look outside every hour. Lastly, children should be kept in fully corrected glasses, not under corrected, and those glasses need to be worn full time.

As we plan the future of education in the age of COVID-19, I firmly believe that schools and policymakers must consider children’s vision needs while designing new initiatives. Schools, teachers, and parents must work together to incorporate eye health strategies that protect children as they learn online. By doing so, we can decrease the chance that a child’s vision becomes compromised from unwittingly staring into a screen for too many hours during the day.
 

Dr. Faktorovich is an ophthalmologist, founder of Pacific Vision Institute in San Francisco, California, and founder of the annual San Francisco Cornea, Cataract, and Refractive Surgery Symposium. She had no relevant financial disclosures. Email her at [email protected].

Early on in the COVID-19 pandemic, clinicians intubated many patients with respiratory insufficiency because of concern for aerosolization with other methods.

“We were concerned that, if we put them on high-flow nasal cannula or a noninvasive ventilation, that we would create aerosols that would then be a risk to clinicians,” Meghan Lane-Fall, MD, MSHP, FCCM, said at a Society for Critical Care Medicine virtual meeting called COVID-19: What’s Next. “However, we’ve gotten much more comfortable with infection control. We’ve gotten much more comfortable with controlling these aerosols, with making sure that our clinicians are protected with the appropriate protective equipment. We’ve also realized that patients who end up becoming intubated have really poor outcomes, so we’ve looked at our practice critically and tried to figure out how to support patients noninvasively when that’s possible.”
 

Respiratory support options

According to Dr. Lane-Fall, an associate professor of anesthesiology and critical care at the University of Pennsylvania, Philadelphia, there are two basic types of respiratory support in patients with moderate, severe, or critical COVID-19: noninvasive and invasive. Noninvasive options include CPAP or BiPAP which can be delivered through nasal pillows, masks, and helmets, as well as high-flow nasal oxygen. Invasive options include endotracheal intubation, tracheostomy, and extracorporeal membrane oxygenation (ECMO), usually the veno-venous (VV) form. “But it’s uncommon to need VV ECMO, even in patients who have critical COVID-19,” she said.

Factors that favor noninvasive ventilation include stably high oxygen requirements, normal mental status, ward location of care, and moderate to severe COVID-19. Factors that favor invasive ventilation include someone who’s deteriorating rapidly, “whose oxygen requirements aren’t stable or who is cardiopulmonary compromised,” said Dr. Lane-Fall, who is also co–medical director of the Trauma Surgery Intensive Care Unit at Penn Presbyterian Medical Center, also in Philadelphia. Other factors include the need for other invasive procedures such as surgery or if they have severe to critical COVID-19, “not just pneumonia, but [illness that’s] progressing into [acute respiratory distress syndrome],” she said.

Indications for urgent endotracheal intubation as opposed to giving a trial of noninvasive ventilation or high-flow nasal oxygen include altered mental status, inability to protect airway, copious amounts of secretions, a Glasgow Coma Scale score of less than 8, severe respiratory acidosis, hypopnea or apnea, shock, or an inability to tolerate noninvasive support. “This is a relative contraindication,” Dr. Lane-Fall said. “I’ve certainly talked people through the BiPAP mask or the helmet. If you tell a patient, ‘I don’t want to have to put in a breathing tube; I want to maintain you on this,’ often they’ll be able to work through it.”
 

Safety precautions

Aerosolizing procedures require attention to location, personnel, and equipment, including personal protective equipment (PPE), said Dr. Lane-Fall, who is an anesthesiologist by training. “When you are intubating someone, whether they have COVID-19 or not, you are sort of in the belly of the beast,” she said. “You are very exposed to secretions that occur at the time of endotracheal intubation. That’s why it’s important for us to have PPE and barriers to protect ourselves from potential exposure to aerosols during the care of patients with COVID-19.”

In February 2020, the non-for-profit Anesthesia Patient Safety Foundation published recommendations for airway management in patients with suspected COVID-19. A separate guidance was published the British Journal of Anaesthesiology based on emergency tracheal intubation in 202 patients with COVID-19 in Wuhan, China. “The idea here is that you want to intubate under controlled conditions,” said Dr. Lane-Fall, who is an author of the guidance. “You want to use the most experienced operator. You want to have full PPE, including an N95 mask, or something more protective like a powered air purifying respirator or an N95 mask with a face shield. You want the eyes, nose, and mouth of the operator covered completely.”

CPR, another aerosolizing procedure, requires vigilant safety precautions as well. “We struggled with this a little bit at our institution, because our inclination as intensivists when someone is pulseless is to run into the room and start chest compressions and to start resuscitation,” Dr. Lane-Fall said. “But the act of chest compression itself can create aerosols that can present risk to clinicians. We had to tell our clinicians that they have to put on PPE before they do CPR. The buzz phrase here is that there is no emergency in a pandemic. The idea here is that the good of that one patient is outweighed by the good of all the other patients that you could care for if you didn’t have COVID-19 as a clinician. So we have had to encourage our staff to put on PPE first before attending to patients first, even if it delays patient care. Once you have donned PPE, when you’re administering CPR, the number of staff should be minimized. You should have a compressor, and someone to relieve the compressor, and a code leader, someone tending to the airway. But in general, anyone who’s not actively involved should not be in the room.”
 

Risks during extubation

Extubation of COVID-19 patients is also an aerosolizing procedure not just because you’re pulling an endotracheal tube out of the airway but because coughing is a normal part of extubation. “We’ve had to be careful with how we approach extubation in COVID-19 patients,” Dr. Lane-Fall said. “Ideally you’re doing this in a negative pressure environment. We have also had to use full PPE, covering the eyes and face, and putting on a gown for precaution.”

Reintubation of COVID-19 patients is not uncommon. She and her colleagues at Penn Medicine created procedures for having intubators at the ready outside the room in case the patient were to decompensate clinically. “Another thing we learned is that it’s useful to do a leak test prior to extubation, because there may be airway edema related to prolonged intubation in these patients,” Dr. Lane-Fall said. “We found that, if a leak is absent on checking the cuff leak, the use of steroids for a day or 2 may help decrease airway edema. That improves the chances of extubation success.”
 

Strategies for aerosol containment

She concluded her remarks by reviewing airway control adjuncts and clinician safety. This includes physically isolating COVID-19 patients in negative pressure rooms and avoiding and minimizing aerosols, including the use of rapid intubation, “where we induce anesthesia for intubation but we don’t bag-mask the patient because that creates aerosols,” she said. The Anesthesia Patient Safety Foundation guidelines advocate for the use of video laryngoscopy so that you can visualize the glottis easily “and make sure that you successfully intubate the glottis and not the esophagus,” she said.

A smart strategy for aerosol containment is to use the most experienced laryngoscopist available. “If you are in a teaching program, ideally you’re using your most experienced resident, or you’re using fellows or attending physicians,” Dr. Lane-Fall said. “This is not the space for an inexperienced learner.”

Another way to make intubation faster and easier in COVID-19 patients is to use an intubation box, which features a plexiglass shield that enables the intubator to use their hands to get in the patient’s airway while being protected from viral droplets generated during intubation. The box can be cleaned after each use. Blueprints for an open source intubation box can be found at http://www.intubationbox.com.

Expert view on aerosol containment in COVID-19

“While there is a dearth of evidence from controlled trials, recommendations mentioned in this story are based on the best available evidence and are in agreement with guidelines from several expert groups,” said David L. Bowton, MD, FCCP, FCCM, of the department of anesthesiology at Wake Forest Baptist Health in Winston-Salem, NC. “The recommendation of Dr. Lane-Fall’s that is perhaps most controversial is the use of an intubation box. Multiple designs for these intubation/aerosol containment devices have been proposed, and the data supporting their ease of use and efficacy has been mixed [See Anaesthesia 2020;75(8):1014-21 and Anaesthesia. 2020. doi: 10.1111/anae.15188]. While bag valve mask ventilation should be avoided if possible, it may be a valuable rescue tool in the severely hypoxemic patient when used with two-person technique to achieve a tight seal and a PEEP valve and an HME over the exhalation port to minimize aerosol spread.

“It cannot be stressed enough that the most skilled individual should be tasked with intubating the patient and as few providers as possible [usually three] should be in the room and have donned full PPE. Negative pressure rooms should be used whenever feasible. Noninvasive ventilation appears safer from an infection control standpoint than initially feared and its use has become more widespread. However, noninvasive ventilation is not without its hazards, and Dr. Lane-Fall’s enumeration of the patient characteristics applicable to the selection of patients for noninvasive ventilation are extremely important. At our institution, the use of noninvasive ventilation and especially high-flow oxygen therapy has increased. Staff have become more comfortable with the donning and doffing of PPE.”

Dr. Lane-Fall reported having no financial disclosures.

[email protected]

Early on in the COVID-19 pandemic, clinicians intubated many patients with respiratory insufficiency because of concern for aerosolization with other methods.

“We were concerned that, if we put them on high-flow nasal cannula or a noninvasive ventilation, that we would create aerosols that would then be a risk to clinicians,” Meghan Lane-Fall, MD, MSHP, FCCM, said at a Society for Critical Care Medicine virtual meeting called COVID-19: What’s Next. “However, we’ve gotten much more comfortable with infection control. We’ve gotten much more comfortable with controlling these aerosols, with making sure that our clinicians are protected with the appropriate protective equipment. We’ve also realized that patients who end up becoming intubated have really poor outcomes, so we’ve looked at our practice critically and tried to figure out how to support patients noninvasively when that’s possible.”
 

Respiratory support options

According to Dr. Lane-Fall, an associate professor of anesthesiology and critical care at the University of Pennsylvania, Philadelphia, there are two basic types of respiratory support in patients with moderate, severe, or critical COVID-19: noninvasive and invasive. Noninvasive options include CPAP or BiPAP which can be delivered through nasal pillows, masks, and helmets, as well as high-flow nasal oxygen. Invasive options include endotracheal intubation, tracheostomy, and extracorporeal membrane oxygenation (ECMO), usually the veno-venous (VV) form. “But it’s uncommon to need VV ECMO, even in patients who have critical COVID-19,” she said.

Factors that favor noninvasive ventilation include stably high oxygen requirements, normal mental status, ward location of care, and moderate to severe COVID-19. Factors that favor invasive ventilation include someone who’s deteriorating rapidly, “whose oxygen requirements aren’t stable or who is cardiopulmonary compromised,” said Dr. Lane-Fall, who is also co–medical director of the Trauma Surgery Intensive Care Unit at Penn Presbyterian Medical Center, also in Philadelphia. Other factors include the need for other invasive procedures such as surgery or if they have severe to critical COVID-19, “not just pneumonia, but [illness that’s] progressing into [acute respiratory distress syndrome],” she said.

Indications for urgent endotracheal intubation as opposed to giving a trial of noninvasive ventilation or high-flow nasal oxygen include altered mental status, inability to protect airway, copious amounts of secretions, a Glasgow Coma Scale score of less than 8, severe respiratory acidosis, hypopnea or apnea, shock, or an inability to tolerate noninvasive support. “This is a relative contraindication,” Dr. Lane-Fall said. “I’ve certainly talked people through the BiPAP mask or the helmet. If you tell a patient, ‘I don’t want to have to put in a breathing tube; I want to maintain you on this,’ often they’ll be able to work through it.”
 

Safety precautions

Aerosolizing procedures require attention to location, personnel, and equipment, including personal protective equipment (PPE), said Dr. Lane-Fall, who is an anesthesiologist by training. “When you are intubating someone, whether they have COVID-19 or not, you are sort of in the belly of the beast,” she said. “You are very exposed to secretions that occur at the time of endotracheal intubation. That’s why it’s important for us to have PPE and barriers to protect ourselves from potential exposure to aerosols during the care of patients with COVID-19.”

In February 2020, the non-for-profit Anesthesia Patient Safety Foundation published recommendations for airway management in patients with suspected COVID-19. A separate guidance was published the British Journal of Anaesthesiology based on emergency tracheal intubation in 202 patients with COVID-19 in Wuhan, China. “The idea here is that you want to intubate under controlled conditions,” said Dr. Lane-Fall, who is an author of the guidance. “You want to use the most experienced operator. You want to have full PPE, including an N95 mask, or something more protective like a powered air purifying respirator or an N95 mask with a face shield. You want the eyes, nose, and mouth of the operator covered completely.”

CPR, another aerosolizing procedure, requires vigilant safety precautions as well. “We struggled with this a little bit at our institution, because our inclination as intensivists when someone is pulseless is to run into the room and start chest compressions and to start resuscitation,” Dr. Lane-Fall said. “But the act of chest compression itself can create aerosols that can present risk to clinicians. We had to tell our clinicians that they have to put on PPE before they do CPR. The buzz phrase here is that there is no emergency in a pandemic. The idea here is that the good of that one patient is outweighed by the good of all the other patients that you could care for if you didn’t have COVID-19 as a clinician. So we have had to encourage our staff to put on PPE first before attending to patients first, even if it delays patient care. Once you have donned PPE, when you’re administering CPR, the number of staff should be minimized. You should have a compressor, and someone to relieve the compressor, and a code leader, someone tending to the airway. But in general, anyone who’s not actively involved should not be in the room.”
 

Risks during extubation

Extubation of COVID-19 patients is also an aerosolizing procedure not just because you’re pulling an endotracheal tube out of the airway but because coughing is a normal part of extubation. “We’ve had to be careful with how we approach extubation in COVID-19 patients,” Dr. Lane-Fall said. “Ideally you’re doing this in a negative pressure environment. We have also had to use full PPE, covering the eyes and face, and putting on a gown for precaution.”

Reintubation of COVID-19 patients is not uncommon. She and her colleagues at Penn Medicine created procedures for having intubators at the ready outside the room in case the patient were to decompensate clinically. “Another thing we learned is that it’s useful to do a leak test prior to extubation, because there may be airway edema related to prolonged intubation in these patients,” Dr. Lane-Fall said. “We found that, if a leak is absent on checking the cuff leak, the use of steroids for a day or 2 may help decrease airway edema. That improves the chances of extubation success.”
 

Strategies for aerosol containment

She concluded her remarks by reviewing airway control adjuncts and clinician safety. This includes physically isolating COVID-19 patients in negative pressure rooms and avoiding and minimizing aerosols, including the use of rapid intubation, “where we induce anesthesia for intubation but we don’t bag-mask the patient because that creates aerosols,” she said. The Anesthesia Patient Safety Foundation guidelines advocate for the use of video laryngoscopy so that you can visualize the glottis easily “and make sure that you successfully intubate the glottis and not the esophagus,” she said.

A smart strategy for aerosol containment is to use the most experienced laryngoscopist available. “If you are in a teaching program, ideally you’re using your most experienced resident, or you’re using fellows or attending physicians,” Dr. Lane-Fall said. “This is not the space for an inexperienced learner.”

Another way to make intubation faster and easier in COVID-19 patients is to use an intubation box, which features a plexiglass shield that enables the intubator to use their hands to get in the patient’s airway while being protected from viral droplets generated during intubation. The box can be cleaned after each use. Blueprints for an open source intubation box can be found at http://www.intubationbox.com.

Expert view on aerosol containment in COVID-19

“While there is a dearth of evidence from controlled trials, recommendations mentioned in this story are based on the best available evidence and are in agreement with guidelines from several expert groups,” said David L. Bowton, MD, FCCP, FCCM, of the department of anesthesiology at Wake Forest Baptist Health in Winston-Salem, NC. “The recommendation of Dr. Lane-Fall’s that is perhaps most controversial is the use of an intubation box. Multiple designs for these intubation/aerosol containment devices have been proposed, and the data supporting their ease of use and efficacy has been mixed [See Anaesthesia 2020;75(8):1014-21 and Anaesthesia. 2020. doi: 10.1111/anae.15188]. While bag valve mask ventilation should be avoided if possible, it may be a valuable rescue tool in the severely hypoxemic patient when used with two-person technique to achieve a tight seal and a PEEP valve and an HME over the exhalation port to minimize aerosol spread.

“It cannot be stressed enough that the most skilled individual should be tasked with intubating the patient and as few providers as possible [usually three] should be in the room and have donned full PPE. Negative pressure rooms should be used whenever feasible. Noninvasive ventilation appears safer from an infection control standpoint than initially feared and its use has become more widespread. However, noninvasive ventilation is not without its hazards, and Dr. Lane-Fall’s enumeration of the patient characteristics applicable to the selection of patients for noninvasive ventilation are extremely important. At our institution, the use of noninvasive ventilation and especially high-flow oxygen therapy has increased. Staff have become more comfortable with the donning and doffing of PPE.”

Dr. Lane-Fall reported having no financial disclosures.

[email protected]

Early on in the COVID-19 pandemic, clinicians intubated many patients with respiratory insufficiency because of concern for aerosolization with other methods.

“We were concerned that, if we put them on high-flow nasal cannula or a noninvasive ventilation, that we would create aerosols that would then be a risk to clinicians,” Meghan Lane-Fall, MD, MSHP, FCCM, said at a Society for Critical Care Medicine virtual meeting called COVID-19: What’s Next. “However, we’ve gotten much more comfortable with infection control. We’ve gotten much more comfortable with controlling these aerosols, with making sure that our clinicians are protected with the appropriate protective equipment. We’ve also realized that patients who end up becoming intubated have really poor outcomes, so we’ve looked at our practice critically and tried to figure out how to support patients noninvasively when that’s possible.”
 

Respiratory support options

According to Dr. Lane-Fall, an associate professor of anesthesiology and critical care at the University of Pennsylvania, Philadelphia, there are two basic types of respiratory support in patients with moderate, severe, or critical COVID-19: noninvasive and invasive. Noninvasive options include CPAP or BiPAP which can be delivered through nasal pillows, masks, and helmets, as well as high-flow nasal oxygen. Invasive options include endotracheal intubation, tracheostomy, and extracorporeal membrane oxygenation (ECMO), usually the veno-venous (VV) form. “But it’s uncommon to need VV ECMO, even in patients who have critical COVID-19,” she said.

Factors that favor noninvasive ventilation include stably high oxygen requirements, normal mental status, ward location of care, and moderate to severe COVID-19. Factors that favor invasive ventilation include someone who’s deteriorating rapidly, “whose oxygen requirements aren’t stable or who is cardiopulmonary compromised,” said Dr. Lane-Fall, who is also co–medical director of the Trauma Surgery Intensive Care Unit at Penn Presbyterian Medical Center, also in Philadelphia. Other factors include the need for other invasive procedures such as surgery or if they have severe to critical COVID-19, “not just pneumonia, but [illness that’s] progressing into [acute respiratory distress syndrome],” she said.

Indications for urgent endotracheal intubation as opposed to giving a trial of noninvasive ventilation or high-flow nasal oxygen include altered mental status, inability to protect airway, copious amounts of secretions, a Glasgow Coma Scale score of less than 8, severe respiratory acidosis, hypopnea or apnea, shock, or an inability to tolerate noninvasive support. “This is a relative contraindication,” Dr. Lane-Fall said. “I’ve certainly talked people through the BiPAP mask or the helmet. If you tell a patient, ‘I don’t want to have to put in a breathing tube; I want to maintain you on this,’ often they’ll be able to work through it.”
 

Safety precautions

Aerosolizing procedures require attention to location, personnel, and equipment, including personal protective equipment (PPE), said Dr. Lane-Fall, who is an anesthesiologist by training. “When you are intubating someone, whether they have COVID-19 or not, you are sort of in the belly of the beast,” she said. “You are very exposed to secretions that occur at the time of endotracheal intubation. That’s why it’s important for us to have PPE and barriers to protect ourselves from potential exposure to aerosols during the care of patients with COVID-19.”

In February 2020, the non-for-profit Anesthesia Patient Safety Foundation published recommendations for airway management in patients with suspected COVID-19. A separate guidance was published the British Journal of Anaesthesiology based on emergency tracheal intubation in 202 patients with COVID-19 in Wuhan, China. “The idea here is that you want to intubate under controlled conditions,” said Dr. Lane-Fall, who is an author of the guidance. “You want to use the most experienced operator. You want to have full PPE, including an N95 mask, or something more protective like a powered air purifying respirator or an N95 mask with a face shield. You want the eyes, nose, and mouth of the operator covered completely.”

CPR, another aerosolizing procedure, requires vigilant safety precautions as well. “We struggled with this a little bit at our institution, because our inclination as intensivists when someone is pulseless is to run into the room and start chest compressions and to start resuscitation,” Dr. Lane-Fall said. “But the act of chest compression itself can create aerosols that can present risk to clinicians. We had to tell our clinicians that they have to put on PPE before they do CPR. The buzz phrase here is that there is no emergency in a pandemic. The idea here is that the good of that one patient is outweighed by the good of all the other patients that you could care for if you didn’t have COVID-19 as a clinician. So we have had to encourage our staff to put on PPE first before attending to patients first, even if it delays patient care. Once you have donned PPE, when you’re administering CPR, the number of staff should be minimized. You should have a compressor, and someone to relieve the compressor, and a code leader, someone tending to the airway. But in general, anyone who’s not actively involved should not be in the room.”
 

Risks during extubation

Extubation of COVID-19 patients is also an aerosolizing procedure not just because you’re pulling an endotracheal tube out of the airway but because coughing is a normal part of extubation. “We’ve had to be careful with how we approach extubation in COVID-19 patients,” Dr. Lane-Fall said. “Ideally you’re doing this in a negative pressure environment. We have also had to use full PPE, covering the eyes and face, and putting on a gown for precaution.”

Reintubation of COVID-19 patients is not uncommon. She and her colleagues at Penn Medicine created procedures for having intubators at the ready outside the room in case the patient were to decompensate clinically. “Another thing we learned is that it’s useful to do a leak test prior to extubation, because there may be airway edema related to prolonged intubation in these patients,” Dr. Lane-Fall said. “We found that, if a leak is absent on checking the cuff leak, the use of steroids for a day or 2 may help decrease airway edema. That improves the chances of extubation success.”
 

Strategies for aerosol containment

She concluded her remarks by reviewing airway control adjuncts and clinician safety. This includes physically isolating COVID-19 patients in negative pressure rooms and avoiding and minimizing aerosols, including the use of rapid intubation, “where we induce anesthesia for intubation but we don’t bag-mask the patient because that creates aerosols,” she said. The Anesthesia Patient Safety Foundation guidelines advocate for the use of video laryngoscopy so that you can visualize the glottis easily “and make sure that you successfully intubate the glottis and not the esophagus,” she said.

A smart strategy for aerosol containment is to use the most experienced laryngoscopist available. “If you are in a teaching program, ideally you’re using your most experienced resident, or you’re using fellows or attending physicians,” Dr. Lane-Fall said. “This is not the space for an inexperienced learner.”

Another way to make intubation faster and easier in COVID-19 patients is to use an intubation box, which features a plexiglass shield that enables the intubator to use their hands to get in the patient’s airway while being protected from viral droplets generated during intubation. The box can be cleaned after each use. Blueprints for an open source intubation box can be found at http://www.intubationbox.com.

Expert view on aerosol containment in COVID-19

“While there is a dearth of evidence from controlled trials, recommendations mentioned in this story are based on the best available evidence and are in agreement with guidelines from several expert groups,” said David L. Bowton, MD, FCCP, FCCM, of the department of anesthesiology at Wake Forest Baptist Health in Winston-Salem, NC. “The recommendation of Dr. Lane-Fall’s that is perhaps most controversial is the use of an intubation box. Multiple designs for these intubation/aerosol containment devices have been proposed, and the data supporting their ease of use and efficacy has been mixed [See Anaesthesia 2020;75(8):1014-21 and Anaesthesia. 2020. doi: 10.1111/anae.15188]. While bag valve mask ventilation should be avoided if possible, it may be a valuable rescue tool in the severely hypoxemic patient when used with two-person technique to achieve a tight seal and a PEEP valve and an HME over the exhalation port to minimize aerosol spread.

“It cannot be stressed enough that the most skilled individual should be tasked with intubating the patient and as few providers as possible [usually three] should be in the room and have donned full PPE. Negative pressure rooms should be used whenever feasible. Noninvasive ventilation appears safer from an infection control standpoint than initially feared and its use has become more widespread. However, noninvasive ventilation is not without its hazards, and Dr. Lane-Fall’s enumeration of the patient characteristics applicable to the selection of patients for noninvasive ventilation are extremely important. At our institution, the use of noninvasive ventilation and especially high-flow oxygen therapy has increased. Staff have become more comfortable with the donning and doffing of PPE.”

Dr. Lane-Fall reported having no financial disclosures.

[email protected]

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

In an earlier article, we looked at the meaning of the P value.¹ This time we will look at another crucial statistical concept: that of confounding.

Confounding, as the name implies, is the recognition that crude associations may not reflect reality, but may instead be the result of outside factors. To illustrate, imagine that you want to study whether smoking increases the risk of death (in statistical terms, smoking is the exposure, and death is the outcome). You follow 5,000 people who smoke and 5,000 people who do not smoke for 10 years. At the end of the follow-up you find that about 40% of nonsmokers died, compared with only 10% of smokers. What do you conclude? At face value it would seem that smoking prevents death. However, before reaching this conclusion you might want to look at other factors. A look at the dataset shows that the average baseline age among nonsmokers was 60 years, whereas among smokers was 40 years. Could this be the cause of the results? You repeat the analysis based on strata of age (i.e., you compare smokers who were aged 60-70 years at baseline with nonsmokers who were aged 60-70 years, smokers who were aged 50-60 years with nonsmokers who were aged 50-60 years, and so on). What you find is that, for each category of age, the percentage of death among smokers was higher. Hence, you now reach the opposite conclusion, namely that smoking does increase the risk of death.

What happened? Why the different result? The answer is that, in this case, age was a confounder. What we initially thought was the effect of smoking was, in reality, at least in part, the effect of age. Overall, more deaths occurred among nonsmokers in the first analysis because they were older at baseline. When we compare people with similar age but who differ on smoking status, then the difference in mortality between them is not because of age (they have the same age) but smoking. Thus, in the second analysis we took age into account, or, in statistical terms, we adjusted for age, whereas the first analysis was, in statistical terms, an unadjusted or crude analysis. We should always be aware of studies with only crude results, because they might be biased/misleading.²

In the example above, age is not the only factor that might influence mortality. Alcohol or drug use, cancer or heart disease, body mass index, or physical activity can also influence death, independently of smoking. How to adjust for all these factors? We cannot do stratified analyses as we did above, because the strata would be too many. The solution is to do a multivariable regression analysis. This is a statistical tool to adjust for multiple factors (or variables) at the same time. When we adjust for all these factors, we are comparing the effect of smoking in people who are the same with regard to all these factors but who differ on smoking status. In statistical terms, we study the effect of smoking, keeping everything else constant. In this way we “isolate” the effect of smoking on death by taking into account all other factors, or, in statistical terms, we study the effect of smoking independently of other factors.

How many factors should be included in a multivariable analysis? As a general rule, the more the better, to reduce confounding. However, the number of variables to include in a regression model is limited by the sample size. The general rule of thumb is that, for every 10 events (for dichotomous outcomes) or 10 people (for continuous outcomes), we can add one variable in the model. If we add more variables than that, then in statistical terms the model becomes overfitted (i.e., it gives results that are specific to that dataset, but may not be applicable to other datasets). Overfitted models can be as biased/misleading as crude models.³

References

1. The P value: What to make of it? A simple guide for the uninitiated. GI and Hepatology News. 2019 Sep 23. https://www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated

2. VanderWeele TJ et al. Ann Stat. 2013 Feb;41(1):196-220.

3. Concato J et al. Ann Intern Med. 1993 Feb 1;118(3):201-10.

4. VanderWeele TJ et al. Ann Intern Med. 2017 Aug 15;167(4):268-74.

Dr. Jovani is a therapeutic endoscopy fellow in the division of gastroenterology and hepatology at Johns Hopkins Hospital, Baltimore.

In an earlier article, we looked at the meaning of the P value.¹ This time we will look at another crucial statistical concept: that of confounding.

Confounding, as the name implies, is the recognition that crude associations may not reflect reality, but may instead be the result of outside factors. To illustrate, imagine that you want to study whether smoking increases the risk of death (in statistical terms, smoking is the exposure, and death is the outcome). You follow 5,000 people who smoke and 5,000 people who do not smoke for 10 years. At the end of the follow-up you find that about 40% of nonsmokers died, compared with only 10% of smokers. What do you conclude? At face value it would seem that smoking prevents death. However, before reaching this conclusion you might want to look at other factors. A look at the dataset shows that the average baseline age among nonsmokers was 60 years, whereas among smokers was 40 years. Could this be the cause of the results? You repeat the analysis based on strata of age (i.e., you compare smokers who were aged 60-70 years at baseline with nonsmokers who were aged 60-70 years, smokers who were aged 50-60 years with nonsmokers who were aged 50-60 years, and so on). What you find is that, for each category of age, the percentage of death among smokers was higher. Hence, you now reach the opposite conclusion, namely that smoking does increase the risk of death.

What happened? Why the different result? The answer is that, in this case, age was a confounder. What we initially thought was the effect of smoking was, in reality, at least in part, the effect of age. Overall, more deaths occurred among nonsmokers in the first analysis because they were older at baseline. When we compare people with similar age but who differ on smoking status, then the difference in mortality between them is not because of age (they have the same age) but smoking. Thus, in the second analysis we took age into account, or, in statistical terms, we adjusted for age, whereas the first analysis was, in statistical terms, an unadjusted or crude analysis. We should always be aware of studies with only crude results, because they might be biased/misleading.²

In the example above, age is not the only factor that might influence mortality. Alcohol or drug use, cancer or heart disease, body mass index, or physical activity can also influence death, independently of smoking. How to adjust for all these factors? We cannot do stratified analyses as we did above, because the strata would be too many. The solution is to do a multivariable regression analysis. This is a statistical tool to adjust for multiple factors (or variables) at the same time. When we adjust for all these factors, we are comparing the effect of smoking in people who are the same with regard to all these factors but who differ on smoking status. In statistical terms, we study the effect of smoking, keeping everything else constant. In this way we “isolate” the effect of smoking on death by taking into account all other factors, or, in statistical terms, we study the effect of smoking independently of other factors.

How many factors should be included in a multivariable analysis? As a general rule, the more the better, to reduce confounding. However, the number of variables to include in a regression model is limited by the sample size. The general rule of thumb is that, for every 10 events (for dichotomous outcomes) or 10 people (for continuous outcomes), we can add one variable in the model. If we add more variables than that, then in statistical terms the model becomes overfitted (i.e., it gives results that are specific to that dataset, but may not be applicable to other datasets). Overfitted models can be as biased/misleading as crude models.³

References

1. The P value: What to make of it? A simple guide for the uninitiated. GI and Hepatology News. 2019 Sep 23. https://www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated

2. VanderWeele TJ et al. Ann Stat. 2013 Feb;41(1):196-220.

3. Concato J et al. Ann Intern Med. 1993 Feb 1;118(3):201-10.

4. VanderWeele TJ et al. Ann Intern Med. 2017 Aug 15;167(4):268-74.

Dr. Jovani is a therapeutic endoscopy fellow in the division of gastroenterology and hepatology at Johns Hopkins Hospital, Baltimore.

In an earlier article, we looked at the meaning of the P value.¹ This time we will look at another crucial statistical concept: that of confounding.

Confounding, as the name implies, is the recognition that crude associations may not reflect reality, but may instead be the result of outside factors. To illustrate, imagine that you want to study whether smoking increases the risk of death (in statistical terms, smoking is the exposure, and death is the outcome). You follow 5,000 people who smoke and 5,000 people who do not smoke for 10 years. At the end of the follow-up you find that about 40% of nonsmokers died, compared with only 10% of smokers. What do you conclude? At face value it would seem that smoking prevents death. However, before reaching this conclusion you might want to look at other factors. A look at the dataset shows that the average baseline age among nonsmokers was 60 years, whereas among smokers was 40 years. Could this be the cause of the results? You repeat the analysis based on strata of age (i.e., you compare smokers who were aged 60-70 years at baseline with nonsmokers who were aged 60-70 years, smokers who were aged 50-60 years with nonsmokers who were aged 50-60 years, and so on). What you find is that, for each category of age, the percentage of death among smokers was higher. Hence, you now reach the opposite conclusion, namely that smoking does increase the risk of death.

What happened? Why the different result? The answer is that, in this case, age was a confounder. What we initially thought was the effect of smoking was, in reality, at least in part, the effect of age. Overall, more deaths occurred among nonsmokers in the first analysis because they were older at baseline. When we compare people with similar age but who differ on smoking status, then the difference in mortality between them is not because of age (they have the same age) but smoking. Thus, in the second analysis we took age into account, or, in statistical terms, we adjusted for age, whereas the first analysis was, in statistical terms, an unadjusted or crude analysis. We should always be aware of studies with only crude results, because they might be biased/misleading.²

In the example above, age is not the only factor that might influence mortality. Alcohol or drug use, cancer or heart disease, body mass index, or physical activity can also influence death, independently of smoking. How to adjust for all these factors? We cannot do stratified analyses as we did above, because the strata would be too many. The solution is to do a multivariable regression analysis. This is a statistical tool to adjust for multiple factors (or variables) at the same time. When we adjust for all these factors, we are comparing the effect of smoking in people who are the same with regard to all these factors but who differ on smoking status. In statistical terms, we study the effect of smoking, keeping everything else constant. In this way we “isolate” the effect of smoking on death by taking into account all other factors, or, in statistical terms, we study the effect of smoking independently of other factors.

How many factors should be included in a multivariable analysis? As a general rule, the more the better, to reduce confounding. However, the number of variables to include in a regression model is limited by the sample size. The general rule of thumb is that, for every 10 events (for dichotomous outcomes) or 10 people (for continuous outcomes), we can add one variable in the model. If we add more variables than that, then in statistical terms the model becomes overfitted (i.e., it gives results that are specific to that dataset, but may not be applicable to other datasets). Overfitted models can be as biased/misleading as crude models.³

References

1. The P value: What to make of it? A simple guide for the uninitiated. GI and Hepatology News. 2019 Sep 23. https://www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated

2. VanderWeele TJ et al. Ann Stat. 2013 Feb;41(1):196-220.

3. Concato J et al. Ann Intern Med. 1993 Feb 1;118(3):201-10.

4. VanderWeele TJ et al. Ann Intern Med. 2017 Aug 15;167(4):268-74.

Dr. Jovani is a therapeutic endoscopy fellow in the division of gastroenterology and hepatology at Johns Hopkins Hospital, Baltimore.

One year into the implementation of the Mission Act, the US Department of Veterans Affairs (VA) continues to expand a wide-ranging third-party-administered program to boost the access of veterans to the civilian medical system, a VA official told colleagues at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO). “VA has given to the third-party administrators what they do well, which is payment of claims, and VA has taken back what we think we can do better—scheduling, care coordination, and customer service,” said Elizabeth Brill, MD, MBA, chief medical officer and senior adviser to the acting assistant undersecretary for Health for Community Care.

            The 2 third-party contractors that run the Community Care Network (CCN) are Optum and TriWest. Both companies now proces patients at all VA medical facilities in the continental US. Optum serves all the states that are entirely (or mainly) in the Central and Eastern Time Zones—except for Texas—plus Puerto Rico, Washington D.C., and the US Virgin Islands. TriWest serves Texas, Hawaii, and the states that are entirely (or mainly) in the Mountain and Pacific Time Zones. The VA has not yet assigned any contractor for Alaska, Guam, American Samoa, and the Northern Mariana Islands.

“We have tried to consolidate as much as possible into the Community Care Network, pulling in a lot of services that were not previously covered, but it’s still not covering 100% of all services that veterans need outside VA medical centers,” said Brill.

Although the VA continues to rely on Veterans Care Agreements, in which health care providers contract directly with the VA, “the main focus of community care is the Community Care Network.” Said Brill. In a pair of regions—encompassing the Midwest, Northeast, and a few other states—90% of private health services are now provided through the network, she said.

One benefit of the new system is a better experience for the health care providers who work with Optum and TriWest. These administrators are responsible for finding providers and providing them with credentials based on appropriate criteria, Brill said. “In prior days, VA paid community providers directly, and some of you may be familiar with the delays that occurred in the system,” she said. “In the new system, we have third-party administrators who pay the providers quickly, and then VA pays them.”

Urgent care services are now available through CCN in most of the continental US and will be expanded to Texas, the Mountain region and the West by the end of September, she said. “We’ve been very pleased to see the response.” Meanwhile, flu shots for enrolled veterans are now available through the system via 60,000 locations.

There are requirements for private health care providers: They must meet new training requirements and submit claims within 180 days. Patients also must meet standards to get community care. For example, patients are eligible for access if the VA can’t serve them within a 30-minute drive time for primary care and mental health care and a 60-minute drive time for specialty care. Similarly, veterans are eligible if they cannot get an appointment within 20 days for primary and mental health care and 28 days for specialty care.

However, Brill insisted, the Mission Act is “not a move toward privatization. Internal VA care is just as important as external VA care,” she said. “This just gives them more choice.”

Brill also noted that there’s more to the Mission Act than expanded access. For example, an expansion of the Program of Comprehensive Assistance for Family Caregivers Program “will start kicking in this fall and the winter,” she said. It will include families of veterans from all eras of service.

The act also is designed to improve infrastructure, although the coronavirus pandemic may disrupt timing, she said. And, she added, it will strengthen the VA’s ability to recruit and keep health care providers through projects like a new scholarship program and more access to medical education debt reduction. 

One year into the implementation of the Mission Act, the US Department of Veterans Affairs (VA) continues to expand a wide-ranging third-party-administered program to boost the access of veterans to the civilian medical system, a VA official told colleagues at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO). “VA has given to the third-party administrators what they do well, which is payment of claims, and VA has taken back what we think we can do better—scheduling, care coordination, and customer service,” said Elizabeth Brill, MD, MBA, chief medical officer and senior adviser to the acting assistant undersecretary for Health for Community Care.

            The 2 third-party contractors that run the Community Care Network (CCN) are Optum and TriWest. Both companies now proces patients at all VA medical facilities in the continental US. Optum serves all the states that are entirely (or mainly) in the Central and Eastern Time Zones—except for Texas—plus Puerto Rico, Washington D.C., and the US Virgin Islands. TriWest serves Texas, Hawaii, and the states that are entirely (or mainly) in the Mountain and Pacific Time Zones. The VA has not yet assigned any contractor for Alaska, Guam, American Samoa, and the Northern Mariana Islands.

“We have tried to consolidate as much as possible into the Community Care Network, pulling in a lot of services that were not previously covered, but it’s still not covering 100% of all services that veterans need outside VA medical centers,” said Brill.

Although the VA continues to rely on Veterans Care Agreements, in which health care providers contract directly with the VA, “the main focus of community care is the Community Care Network.” Said Brill. In a pair of regions—encompassing the Midwest, Northeast, and a few other states—90% of private health services are now provided through the network, she said.

One benefit of the new system is a better experience for the health care providers who work with Optum and TriWest. These administrators are responsible for finding providers and providing them with credentials based on appropriate criteria, Brill said. “In prior days, VA paid community providers directly, and some of you may be familiar with the delays that occurred in the system,” she said. “In the new system, we have third-party administrators who pay the providers quickly, and then VA pays them.”

Urgent care services are now available through CCN in most of the continental US and will be expanded to Texas, the Mountain region and the West by the end of September, she said. “We’ve been very pleased to see the response.” Meanwhile, flu shots for enrolled veterans are now available through the system via 60,000 locations.

There are requirements for private health care providers: They must meet new training requirements and submit claims within 180 days. Patients also must meet standards to get community care. For example, patients are eligible for access if the VA can’t serve them within a 30-minute drive time for primary care and mental health care and a 60-minute drive time for specialty care. Similarly, veterans are eligible if they cannot get an appointment within 20 days for primary and mental health care and 28 days for specialty care.

However, Brill insisted, the Mission Act is “not a move toward privatization. Internal VA care is just as important as external VA care,” she said. “This just gives them more choice.”

Brill also noted that there’s more to the Mission Act than expanded access. For example, an expansion of the Program of Comprehensive Assistance for Family Caregivers Program “will start kicking in this fall and the winter,” she said. It will include families of veterans from all eras of service.

The act also is designed to improve infrastructure, although the coronavirus pandemic may disrupt timing, she said. And, she added, it will strengthen the VA’s ability to recruit and keep health care providers through projects like a new scholarship program and more access to medical education debt reduction. 

One year into the implementation of the Mission Act, the US Department of Veterans Affairs (VA) continues to expand a wide-ranging third-party-administered program to boost the access of veterans to the civilian medical system, a VA official told colleagues at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO). “VA has given to the third-party administrators what they do well, which is payment of claims, and VA has taken back what we think we can do better—scheduling, care coordination, and customer service,” said Elizabeth Brill, MD, MBA, chief medical officer and senior adviser to the acting assistant undersecretary for Health for Community Care.

            The 2 third-party contractors that run the Community Care Network (CCN) are Optum and TriWest. Both companies now proces patients at all VA medical facilities in the continental US. Optum serves all the states that are entirely (or mainly) in the Central and Eastern Time Zones—except for Texas—plus Puerto Rico, Washington D.C., and the US Virgin Islands. TriWest serves Texas, Hawaii, and the states that are entirely (or mainly) in the Mountain and Pacific Time Zones. The VA has not yet assigned any contractor for Alaska, Guam, American Samoa, and the Northern Mariana Islands.

“We have tried to consolidate as much as possible into the Community Care Network, pulling in a lot of services that were not previously covered, but it’s still not covering 100% of all services that veterans need outside VA medical centers,” said Brill.

Although the VA continues to rely on Veterans Care Agreements, in which health care providers contract directly with the VA, “the main focus of community care is the Community Care Network.” Said Brill. In a pair of regions—encompassing the Midwest, Northeast, and a few other states—90% of private health services are now provided through the network, she said.

One benefit of the new system is a better experience for the health care providers who work with Optum and TriWest. These administrators are responsible for finding providers and providing them with credentials based on appropriate criteria, Brill said. “In prior days, VA paid community providers directly, and some of you may be familiar with the delays that occurred in the system,” she said. “In the new system, we have third-party administrators who pay the providers quickly, and then VA pays them.”

Urgent care services are now available through CCN in most of the continental US and will be expanded to Texas, the Mountain region and the West by the end of September, she said. “We’ve been very pleased to see the response.” Meanwhile, flu shots for enrolled veterans are now available through the system via 60,000 locations.

There are requirements for private health care providers: They must meet new training requirements and submit claims within 180 days. Patients also must meet standards to get community care. For example, patients are eligible for access if the VA can’t serve them within a 30-minute drive time for primary care and mental health care and a 60-minute drive time for specialty care. Similarly, veterans are eligible if they cannot get an appointment within 20 days for primary and mental health care and 28 days for specialty care.

However, Brill insisted, the Mission Act is “not a move toward privatization. Internal VA care is just as important as external VA care,” she said. “This just gives them more choice.”

Brill also noted that there’s more to the Mission Act than expanded access. For example, an expansion of the Program of Comprehensive Assistance for Family Caregivers Program “will start kicking in this fall and the winter,” she said. It will include families of veterans from all eras of service.

The act also is designed to improve infrastructure, although the coronavirus pandemic may disrupt timing, she said. And, she added, it will strengthen the VA’s ability to recruit and keep health care providers through projects like a new scholarship program and more access to medical education debt reduction. 

A new study has found that late-onset neutropenia is a notably common and occasionally serious occurrence in rituximab-treated patients with autoimmune diseases.

“The literature on late-onset neutropenia – or LON – has, to date, been limited in size and scope,” first author Reza Zonozi, MD, of Massachusetts General Hospital in Boston, said in an interview. “At the Vasculitis and Glomerulonephritis Center at Mass General, we’ve seen a number of cases of LON. Even though most are incidental and can be self-limiting, some can be severe and associated with sepsis. As such, we’ve come to appreciate it as one of the more concerning side effects of rituximab.

“Our hope was to offer a practical analysis of LON, how often it happens, and what it looks like,” he added, “as well as to share our approach to its management.” Their findings were published in Arthritis & Rheumatology.

To investigate the incidence, clinical features and outcomes of LON, the researchers launched a study of 738 adult patients with autoimmune diseases who were being treated with rituximab-induced continuous B-cell depletion. For the purposes of this study, LON was defined as an unexplained absolute neutrophil count of less than 1,000 cells/mcL during the period of B-cell depletion. Regarding disease type, 529 of the patients had antineutrophil cytoplasmic antibody–associated vasculitis (AAV), 73 had membranous nephropathy (MN), 59 had minimal change disease or focal segmental glomerulosclerosis (MCD/FSGS), 24 had lupus nephritis, and 53 had another autoimmune disease. Their average age was 58, and 53% were female.

All patients received a median of eight doses of rituximab – most commonly administered as one 1,000-mg IV dose every 4-6 months – and were in a state of B-cell depletion for a median of 2.5 years. Two months of low-dose daily oral cyclophosphamide was also used concurrently in 70% (n = 515) of patients. Glucocorticoids were used in 95% (n = 698) of patients.

During follow-up, 107 episodes of LON occurred in 71 patients. At 1, 2, and 5 years of continuous B-cell depletion, the incidence of LON was 6.6% (95% confidence interval, 5.0%-8.7%), 7.9% (95% CI, 6.1%-10.2%), and 13.5% (95% CI, 10.4%-17.4%), respectively. The first year following treatment initiation saw a much higher incidence rate of 7.2 per 100 person-years (95% CI, 5.4-9.6), compared with the rate thereafter of 1.5 per 100 person-years (95% CI, 1.0-2.3). LON occurred at a median of 4.1 months (interquartile range, 1.6-23.1) after the first rituximab infusion. The most common treatment for a LON episode was filgrastim.

Of the 107 episodes, 63 (59%) were asymptomatic. No infections were identified in asymptomatic episodes, while infections were identified in all symptomatic episodes. The most common symptom was a fever, and all 30 patients with LON and fever were hospitalized for management of febrile neutropenia. Four of the episodes included gingival soreness, and eight were complicated by sepsis. All the sepsis cases were resolved with standard therapy. One patient died with multiple relapsing LON.

Of the 71 patients with LON, 9 were not rechallenged with rituximab. A total of four of those patients had second LON episodes. Of the 62 patients who were rechallenged, 13 had second LON episodes over a median follow-up period of 2.4 years. The cumulative incidence of recurrent LON at 1, 2, and 5 years after rechallenge was 11.5% (95% CI, 5.6%-22.6%), 23.4% (95% CI, 13.8%-38.2%), and 30.4% (95% CI, 16.9%-50.9%), respectively.

Percentagewise, LON occurred significantly more often in patients with lupus nephritis (25%) than in patients with AAV (10.4%), MN (8.2%), or other diseases (7.6%) (P = .03). LON did not occur in any of the patients with MCD/FSGS. After multivariable analysis, lupus nephritis was associated with higher odds of developing LON (adjusted hazard ratio, 2.96; 95% CI, 1.10-8.01). A multivariable model also found that patients treated with cyclophosphamide and rituximab had higher odds of developing LON, compared with patients who did not receive cyclophosphamide (aHR, 1.98; 95% CI, 1.06-3.71).

 

Still more to learn about what leads to LON

“In large part, these findings quantify what our experience has been with LON in clinical practice,” Dr. Zonozi said. “It is indeed common, it’s often incidental, and most cases are reversible and respond well to treatment. But it can be associated with severe infections, including sepsis, and warrants close monitoring.”

In an interview, Md Yuzaiful Md Yusof, MBChB, PhD, observed that this incidence rate was notably higher than what he’d seen previously. Dr. Md Yusof presented at EULAR Congress 2015 on rituximab and LON, finding that 23 patients (2.5%) from a cohort of 912 developed rituximab-associated neutropenia.

“Most of our cases were in patients with rheumatoid arthritis,” he added, “so it may just be a difference in cohorts.”

Regardless, he applauded additional research in this area, noting that “the etiology of rituximab-associated LON is still unclear. The reasons behind this occurrence need investigating, particularly in regard to severe neutropenia cases. If we can find the predictors of those, it will be extremely helpful for the future of treatment.”

Dr. Zonozi agreed that “more investigation is needed to accurately define the mechanism of LON, which remains unknown. This will likely lead to more targeted strategies to both prevent and treat it.”

The authors acknowledged their study’s limitations, including being a single-center study that relied on retrospective data collection. They also acknowledged that, because the center is a nephrology-based practice, there was a low number of certain diseases like RA, opening up the possibility that “rates of LON are different” in those patients.

Two authors’ work on the study was funded by grants from the National Institutes of Health. The authors disclosed no potential conflicts of interest.

SOURCE: Zonozi R et al. Arthritis Rheumatol. 2020 Sep 6. doi: 10.1002/art.41501.

A new study has found that late-onset neutropenia is a notably common and occasionally serious occurrence in rituximab-treated patients with autoimmune diseases.

“The literature on late-onset neutropenia – or LON – has, to date, been limited in size and scope,” first author Reza Zonozi, MD, of Massachusetts General Hospital in Boston, said in an interview. “At the Vasculitis and Glomerulonephritis Center at Mass General, we’ve seen a number of cases of LON. Even though most are incidental and can be self-limiting, some can be severe and associated with sepsis. As such, we’ve come to appreciate it as one of the more concerning side effects of rituximab.

“Our hope was to offer a practical analysis of LON, how often it happens, and what it looks like,” he added, “as well as to share our approach to its management.” Their findings were published in Arthritis & Rheumatology.

To investigate the incidence, clinical features and outcomes of LON, the researchers launched a study of 738 adult patients with autoimmune diseases who were being treated with rituximab-induced continuous B-cell depletion. For the purposes of this study, LON was defined as an unexplained absolute neutrophil count of less than 1,000 cells/mcL during the period of B-cell depletion. Regarding disease type, 529 of the patients had antineutrophil cytoplasmic antibody–associated vasculitis (AAV), 73 had membranous nephropathy (MN), 59 had minimal change disease or focal segmental glomerulosclerosis (MCD/FSGS), 24 had lupus nephritis, and 53 had another autoimmune disease. Their average age was 58, and 53% were female.

All patients received a median of eight doses of rituximab – most commonly administered as one 1,000-mg IV dose every 4-6 months – and were in a state of B-cell depletion for a median of 2.5 years. Two months of low-dose daily oral cyclophosphamide was also used concurrently in 70% (n = 515) of patients. Glucocorticoids were used in 95% (n = 698) of patients.

During follow-up, 107 episodes of LON occurred in 71 patients. At 1, 2, and 5 years of continuous B-cell depletion, the incidence of LON was 6.6% (95% confidence interval, 5.0%-8.7%), 7.9% (95% CI, 6.1%-10.2%), and 13.5% (95% CI, 10.4%-17.4%), respectively. The first year following treatment initiation saw a much higher incidence rate of 7.2 per 100 person-years (95% CI, 5.4-9.6), compared with the rate thereafter of 1.5 per 100 person-years (95% CI, 1.0-2.3). LON occurred at a median of 4.1 months (interquartile range, 1.6-23.1) after the first rituximab infusion. The most common treatment for a LON episode was filgrastim.

Of the 107 episodes, 63 (59%) were asymptomatic. No infections were identified in asymptomatic episodes, while infections were identified in all symptomatic episodes. The most common symptom was a fever, and all 30 patients with LON and fever were hospitalized for management of febrile neutropenia. Four of the episodes included gingival soreness, and eight were complicated by sepsis. All the sepsis cases were resolved with standard therapy. One patient died with multiple relapsing LON.

Of the 71 patients with LON, 9 were not rechallenged with rituximab. A total of four of those patients had second LON episodes. Of the 62 patients who were rechallenged, 13 had second LON episodes over a median follow-up period of 2.4 years. The cumulative incidence of recurrent LON at 1, 2, and 5 years after rechallenge was 11.5% (95% CI, 5.6%-22.6%), 23.4% (95% CI, 13.8%-38.2%), and 30.4% (95% CI, 16.9%-50.9%), respectively.

Percentagewise, LON occurred significantly more often in patients with lupus nephritis (25%) than in patients with AAV (10.4%), MN (8.2%), or other diseases (7.6%) (P = .03). LON did not occur in any of the patients with MCD/FSGS. After multivariable analysis, lupus nephritis was associated with higher odds of developing LON (adjusted hazard ratio, 2.96; 95% CI, 1.10-8.01). A multivariable model also found that patients treated with cyclophosphamide and rituximab had higher odds of developing LON, compared with patients who did not receive cyclophosphamide (aHR, 1.98; 95% CI, 1.06-3.71).

 

Still more to learn about what leads to LON

“In large part, these findings quantify what our experience has been with LON in clinical practice,” Dr. Zonozi said. “It is indeed common, it’s often incidental, and most cases are reversible and respond well to treatment. But it can be associated with severe infections, including sepsis, and warrants close monitoring.”

In an interview, Md Yuzaiful Md Yusof, MBChB, PhD, observed that this incidence rate was notably higher than what he’d seen previously. Dr. Md Yusof presented at EULAR Congress 2015 on rituximab and LON, finding that 23 patients (2.5%) from a cohort of 912 developed rituximab-associated neutropenia.

“Most of our cases were in patients with rheumatoid arthritis,” he added, “so it may just be a difference in cohorts.”

Regardless, he applauded additional research in this area, noting that “the etiology of rituximab-associated LON is still unclear. The reasons behind this occurrence need investigating, particularly in regard to severe neutropenia cases. If we can find the predictors of those, it will be extremely helpful for the future of treatment.”

Dr. Zonozi agreed that “more investigation is needed to accurately define the mechanism of LON, which remains unknown. This will likely lead to more targeted strategies to both prevent and treat it.”

The authors acknowledged their study’s limitations, including being a single-center study that relied on retrospective data collection. They also acknowledged that, because the center is a nephrology-based practice, there was a low number of certain diseases like RA, opening up the possibility that “rates of LON are different” in those patients.

Two authors’ work on the study was funded by grants from the National Institutes of Health. The authors disclosed no potential conflicts of interest.

SOURCE: Zonozi R et al. Arthritis Rheumatol. 2020 Sep 6. doi: 10.1002/art.41501.

A new study has found that late-onset neutropenia is a notably common and occasionally serious occurrence in rituximab-treated patients with autoimmune diseases.

“The literature on late-onset neutropenia – or LON – has, to date, been limited in size and scope,” first author Reza Zonozi, MD, of Massachusetts General Hospital in Boston, said in an interview. “At the Vasculitis and Glomerulonephritis Center at Mass General, we’ve seen a number of cases of LON. Even though most are incidental and can be self-limiting, some can be severe and associated with sepsis. As such, we’ve come to appreciate it as one of the more concerning side effects of rituximab.

“Our hope was to offer a practical analysis of LON, how often it happens, and what it looks like,” he added, “as well as to share our approach to its management.” Their findings were published in Arthritis & Rheumatology.

To investigate the incidence, clinical features and outcomes of LON, the researchers launched a study of 738 adult patients with autoimmune diseases who were being treated with rituximab-induced continuous B-cell depletion. For the purposes of this study, LON was defined as an unexplained absolute neutrophil count of less than 1,000 cells/mcL during the period of B-cell depletion. Regarding disease type, 529 of the patients had antineutrophil cytoplasmic antibody–associated vasculitis (AAV), 73 had membranous nephropathy (MN), 59 had minimal change disease or focal segmental glomerulosclerosis (MCD/FSGS), 24 had lupus nephritis, and 53 had another autoimmune disease. Their average age was 58, and 53% were female.

All patients received a median of eight doses of rituximab – most commonly administered as one 1,000-mg IV dose every 4-6 months – and were in a state of B-cell depletion for a median of 2.5 years. Two months of low-dose daily oral cyclophosphamide was also used concurrently in 70% (n = 515) of patients. Glucocorticoids were used in 95% (n = 698) of patients.

During follow-up, 107 episodes of LON occurred in 71 patients. At 1, 2, and 5 years of continuous B-cell depletion, the incidence of LON was 6.6% (95% confidence interval, 5.0%-8.7%), 7.9% (95% CI, 6.1%-10.2%), and 13.5% (95% CI, 10.4%-17.4%), respectively. The first year following treatment initiation saw a much higher incidence rate of 7.2 per 100 person-years (95% CI, 5.4-9.6), compared with the rate thereafter of 1.5 per 100 person-years (95% CI, 1.0-2.3). LON occurred at a median of 4.1 months (interquartile range, 1.6-23.1) after the first rituximab infusion. The most common treatment for a LON episode was filgrastim.

Of the 107 episodes, 63 (59%) were asymptomatic. No infections were identified in asymptomatic episodes, while infections were identified in all symptomatic episodes. The most common symptom was a fever, and all 30 patients with LON and fever were hospitalized for management of febrile neutropenia. Four of the episodes included gingival soreness, and eight were complicated by sepsis. All the sepsis cases were resolved with standard therapy. One patient died with multiple relapsing LON.

Of the 71 patients with LON, 9 were not rechallenged with rituximab. A total of four of those patients had second LON episodes. Of the 62 patients who were rechallenged, 13 had second LON episodes over a median follow-up period of 2.4 years. The cumulative incidence of recurrent LON at 1, 2, and 5 years after rechallenge was 11.5% (95% CI, 5.6%-22.6%), 23.4% (95% CI, 13.8%-38.2%), and 30.4% (95% CI, 16.9%-50.9%), respectively.

Percentagewise, LON occurred significantly more often in patients with lupus nephritis (25%) than in patients with AAV (10.4%), MN (8.2%), or other diseases (7.6%) (P = .03). LON did not occur in any of the patients with MCD/FSGS. After multivariable analysis, lupus nephritis was associated with higher odds of developing LON (adjusted hazard ratio, 2.96; 95% CI, 1.10-8.01). A multivariable model also found that patients treated with cyclophosphamide and rituximab had higher odds of developing LON, compared with patients who did not receive cyclophosphamide (aHR, 1.98; 95% CI, 1.06-3.71).

 

Still more to learn about what leads to LON

“In large part, these findings quantify what our experience has been with LON in clinical practice,” Dr. Zonozi said. “It is indeed common, it’s often incidental, and most cases are reversible and respond well to treatment. But it can be associated with severe infections, including sepsis, and warrants close monitoring.”

In an interview, Md Yuzaiful Md Yusof, MBChB, PhD, observed that this incidence rate was notably higher than what he’d seen previously. Dr. Md Yusof presented at EULAR Congress 2015 on rituximab and LON, finding that 23 patients (2.5%) from a cohort of 912 developed rituximab-associated neutropenia.

“Most of our cases were in patients with rheumatoid arthritis,” he added, “so it may just be a difference in cohorts.”

Regardless, he applauded additional research in this area, noting that “the etiology of rituximab-associated LON is still unclear. The reasons behind this occurrence need investigating, particularly in regard to severe neutropenia cases. If we can find the predictors of those, it will be extremely helpful for the future of treatment.”

Dr. Zonozi agreed that “more investigation is needed to accurately define the mechanism of LON, which remains unknown. This will likely lead to more targeted strategies to both prevent and treat it.”

The authors acknowledged their study’s limitations, including being a single-center study that relied on retrospective data collection. They also acknowledged that, because the center is a nephrology-based practice, there was a low number of certain diseases like RA, opening up the possibility that “rates of LON are different” in those patients.

Two authors’ work on the study was funded by grants from the National Institutes of Health. The authors disclosed no potential conflicts of interest.

SOURCE: Zonozi R et al. Arthritis Rheumatol. 2020 Sep 6. doi: 10.1002/art.41501.

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

Researchers have identified five cognitive phenotypes among patients with multiple sclerosis (MS). The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.

Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
 

A battery of clinical and imaging tests

She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).

A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.

The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
 

Phenotypes had specific neural bases

The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.

The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.

On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.

“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
 

A need for longitudinal cohort studies

The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.

“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”

The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”

The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.

[email protected]

SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.

Researchers have identified five cognitive phenotypes among patients with multiple sclerosis (MS). The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.

Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
 

A battery of clinical and imaging tests

She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).

A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.

The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
 

Phenotypes had specific neural bases

The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.

The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.

On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.

“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
 

A need for longitudinal cohort studies

The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.

“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”

The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”

The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.

[email protected]

SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.

Researchers have identified five cognitive phenotypes among patients with multiple sclerosis (MS). The lead researcher described the clinical characteristics and MRI findings unique to each phenotype during a lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Between 40% and 70% of patients with MS have cognitive impairment, and the current results emphasize the importance of cognitive evaluation in clinical assessment, according to the investigators. “The identification of cognitive profiles can drive tailored rehabilitative strategies and introduce a new level in the evidence of disease activity assessment,” said Ermelinda De Meo, MD, a neurologist and PhD student at San Raffaele Hospital in Milan. Physical disability has been a major influence on treatment choices to date, but neurologists should consider that patients with minimal physical disability may have cognitive impairment, she added.

Information processing speed and episodic memory are the most commonly impaired cognitive functions in patients with MS, but executive function, verbal fluency, and visuospatial abilities also can be affected. Defining the neuroanatomical basis of cognitive dysfunction and developing effective strategies for rehabilitation requires a clearer understanding of cognitive deficits on an individual level, said Dr. De Meo.
 

A battery of clinical and imaging tests

She and her colleagues analyzed 1,212 patients with all forms of MS who presented to eight Italian centers. They also included 196 age-, sex-, and education-matched controls in their study. Patients underwent evaluation with the Expanded Disability Status Scale (EDSS) and a neuropsychological assessment that included Rao’s Brief Repeatable Battery and Stroop Test. The investigators also administered the Fatigue Severity Scale (FSS) and Montgomery Åsberg Depression Rating Scale (MADRS).

A subset of 172 patients with MS and 50 healthy controls underwent 3-T MRI. Dr. De Meo and colleagues examined T2 hyperintense and T1 hypointense lesion volumes. In addition, they quantified normalized brain volume, white matter volume, and gray matter volume and performed deep gray matter segmentation.

The subset of patients with MS who underwent MRI was not significantly different from the full cohort of patients with MS in the study, said Dr. De Meo. Because of the relatively small number of subjects who underwent MRI, she and her colleagues used simple MRI measures that are well validated, highly reproducible, and less susceptible to measurement error. “We know that advanced MRI technique could provide additional insights about the neural bases of these phenotypes. However, we can consider our MRI results as a starting point to better address future MRI studies,” she said.
 

Phenotypes had specific neural bases

The mean age did not differ significantly between patients (41.1 years) and controls (40.4 years). The sex ratio also was similar in both groups. Patients’ median EDSS score was 2.0, mean disease duration was 10.5 years, mean FSS score was 14.9, and mean MADRS score was 10.1.

The five cognitive phenotypes among patients with MS were characterized by preserved cognition (19%), mild verbal memory or semantic fluency impairment (30%), mild multidomain impairment (19%), severe attention or executive impairment with mild impairment of other domains (14%), and severe multidomain impairment (18%). Compared with patients with other phenotypes, those with preserved cognition and those with mild verbal memory or semantic fluency impairment were younger and had lower clinical disability and shorter disease duration. Patients with severe multidomain impairment had greater depressive symptoms. Patients with severe attention or executive phenotypes had higher FSS scores.

On MRI, patients with preserved cognition had lower thalamic volume than healthy controls. The researchers compared all other phenotypes to these two groups. Patients with mild verbal memory or semantic fluency impairment had reduced hippocampal volume. Patients with mild multidomain impairment had reduced cortical gray matter volume. Patients with severe attention or executive impairment had higher T2 lesion load. Patients with severe multidomain phenotypes had a broader pattern of atrophy, including decreased volume in the gray matter, white matter, thalamus, hippocampus, putamen, and nucleus accumbens.

“The present findings suggest that specific neural bases can be detected for each phenotype,” said Dr. De Meo. “Advanced and multimodal MRI techniques of analysis could help individuate the neural circuits and the neurotransmitter involved, also suggesting potential targets for the pharmacological treatment of cognitive decline.”
 

A need for longitudinal cohort studies

The study by Dr. De Meo and colleagues continues previous investigations of cognitive phenotypes in MS, which originally considered cognition to be either intact or impaired. Further research could “inform the development of targeted treatments for cognitive dysfunction in MS, which will ultimately bring us closer to a precision medicine model,” said Victoria M. Leavitt, PhD, of Columbia University Medical Center in New York.

“Clearly, we have to acknowledge that cognitive impairment is not a one-size-fits-all problem,” she added. “If a memory problem develops as a downstream consequence of language issues, targeting the hippocampus may not be effective. Separating patients into cognitive phenotype groups may be a key to understanding and identifying neural-level differences that underlie diverse cognitive issues.”

The evolution of cognitive changes over time must be understood clearly, because patients may develop memory impairment by separate pathways (e.g., focal lesions that precipitate hippocampal atrophy versus cortical thinning in parietal regions that result in white-matter disconnections among language regions), said Dr. Leavitt. “Longitudinal cohort studies and ... testable mechanistic models that incorporate multimodal neuroimaging metrics are an essential starting point. Machine-learning methods may also be a useful tool for beginning to look at how these different neuroimaging modalities work together dynamically to yield divergent cognitive phenotypes.”

The study was not supported by external funding. Dr. De Meo reported no relevant disclosures. Dr. Leavitt also reported no relevant disclosures.

[email protected]

SOURCE: De Meo E et al. MSVirtual2020, Abstract YI02.03.

While many transgender individuals develop their gender identity early on in life, medically there may not be any intervention until they hit puberty. For prepubertal children, providing a supportive environment and letting them explore gender expression with haircut, clothing, toys, name, and pronouns may be the main “interventions.” Ensure a safe bathroom and safe spaces at school (and home), and perhaps find an experienced therapist comfortable navigating gender concerns. Supporting the family supports the child and can make all the difference in the world. Often clinics specializing in gender care will see young children to provide this support and follow the child into puberty.

Nosyrevy/Getty Images

Once puberty starts, however, medical interventions can be discussed and puberty blockers are a great place to start, given their reversibility. Having an understanding of how puberty blockers work, the side effects, and timing of blocker use is important to the average pediatric provider as you may see some of these children and be able to intervene by sending them to a specialist early!
 

How do puberty blockers work?

One of the first hormonal signals of puberty is the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH then stimulate sex steroidogenesis (production of estradiol or testosterone) and gametogenesis in the gonads. The most common choice for puberty blockers are GnRH agonists, such as leuprolide (a series of shots) or histrelin (an implantable rod), which have been studied extensively for the treatment of children with central precocious puberty, and more recently gender dysphoria. Interestingly, these medicines actually stimulate gonadotropin release and the overproduction makes the gonadotropin receptors less sensitive.¹ Gradually the production of sex steroids decreases. One of the advantages of puberty blockers is that they are reversible – stop the medication and the effects wear off, allowing one to proceed with natal puberty if one so desires. Gender specialists always start with the most reversible intervention, especially at such a young age. Puberty blockers are like a pause button that gives everyone – patient, clinicians, therapists – time to process, explore, and ensure transition is the right path.

Sexual development should stop on puberty blockers. For those born with ovaries, breasts will not continue to develop and menses will not start if premenarchal or stop soon if postmenarchal. For those born with testicles, testicular and penile enlargement will not proceed, the voice will not deepen, hands will not grow in size, and an “Adam’s apple” will not develop. Preventing these changes may not only prevent future surgeries (mastectomy, tracheal shaving, etc.) but may also be lifesaving given the lack of development as secondary sex characteristics may not develop, thus avoiding telltale signs that one has transitioned physically, particularly for transwomen.
 

What are the side effects of puberty blockers?

Whenever an adolescent is started on puberty blockers, it is important to discuss both the main effects (i.e., cessation of puberty and sexual development) as well as the side effects. There are four main side effect areas that are important to cover: bone health and height, brain development, fertility, and surgical implications.

• Bone health & height. Adolescence is an important time for growth. During adolescence, bones grow both in length, which determines an individual’s height, and in density, which can affect risk of osteoporosis later on in life. Sex steroids are an important factor for both of these issues. Estradiol is responsible for closure of the growth plates and, in general, those born with ovaries enter puberty earlier than those born with testicles, therefore they see higher rates of estradiol earlier, which causes cessation of growth, hence why females are typically shorter than males. Delaying these high levels of estrogen may give transmales (female to male individuals) more time to grow. Conversely, decreasing release of testosterone in transfemales (male to female individuals) and then introducing estradiol at higher levels earlier than they would experience with their natal puberty may stop transfemales from growing much taller than the average cisgender woman. Bone density also is a major concern as the sex steroids are very important for bone mass accretion.^1,2 Studies in transgender individuals using dual-energy x-ray absorptiometry show that, for transmale patients, z scores do decrease but they tend to catch up once gender-affirming hormones are started. For transfemale patients, the z scores don’t decrease as much but also don’t increase as much once estrogen is started.^1,3 It is for these reasons that the Endocrine Society guidelines recommend monitoring bone density both before and while on puberty blockers.^4,5
• Brain development. Adolescence also is an important time for brain development, particularly the areas that focus on executive function. Studies comparing transgender patients on GnRH agonists noted no detrimental effects on higher-order cognitive process associated with a specific task meant to test executive function.⁶ Although not performed on transgender individuals, a study examining girls with central precocious puberty on GnRH agonists found no difference with the control group on auditory and visual memory, response inhibition, spatial ability, behavioral problems, or social competence.⁷
• Fertility. Suspending puberty at an early Sexual Maturity Rating (such as stage 2 or 3) may make it difficult to harvest mature oocytes or spermatozoa, thus compromising long-term fertility, especially once they start on gender-affirming hormones. While some patients may choose to delay starting puberty blockers for the sake of cryopreservation, others may be in too much distress at their pubertal changes to wait. Fertility counseling is thus an important aspect of the discussion with transgender patients considering puberty blockers and/or gender-affirming hormones.
• Surgical implications. The most common “bottom surgery” performed in transfemales is called penile inversion vaginoplasty, which uses the penile and scrotal skin to create a neovagina.⁸ However, one has to have enough penile and scrotal development for this surgery to be successful, which may mean waiting until a patient has reached Sexual Maturity Rating stage 4 before starting blockers. There are alternative surgical options, but one must discuss the risks and benefits of waiting to start blockers with the patient and family.

When can puberty blockers be started?

Patients must meet criteria for gender dysphoria with emergence or worsening with puberty.⁹ Any coexisting conditions (psychological, medical, social) that could interfere with treatment have to be addressed, and both the patient and their guardian must undergo informed consent for treatment.^4,5,10 Puberty blockers cannot be used until after puberty has started, so at least Sexual Maturity Rating stage 2. In the early stages of puberty, hormonally one will see LH rise followed by rise in estradiol and/or testosterone. Consideration for both the development of secondary sex characteristics and associated increased distress or dysphoria as well as surgical implications must be weighed in each individual case. The bottom line is that these medications can be life saving and are reversible, so if a patient and/or family decides to stop them, the effects will wear off and natal puberty will resume.

Dr. Lawlis is an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Diabetes Endocrinol. 2017 Oct. doi: 10.1016/S2213-8587(17)30099-2.

2. Bone. 2010 Feb. doi: 10.1016/j.bone.2009.10.005.

3. J Clin Endocrinol Metab. 2015 Feb. doi: 10.1210/jc.2014-2439.

4. J Clin Endocrinol Metab. 2009 Sep. doi: 10.1210/jc.2009-0345.

5. J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658.

6. Psychoneuroendocrinology. 2015 Jun. doi: 10.1016/j.psyneuen.2015.03.007.

7. Front Psychol. 2016 Jul. doi: 10.3389/fpsyg.2016.01053.

8. Sex Med Rev. 2017 Jan. doi: 10.1016/j.sxmr.2016.08.001.

9. “Diagnostic and Statistical Manual of Mental Disorders,” 5th ed. (Arlington, Va.: American Psychiatric Association, 2013).

10. Int J Transgend. 2012. doi: 10.1080/15532739.2011.700873.

While many transgender individuals develop their gender identity early on in life, medically there may not be any intervention until they hit puberty. For prepubertal children, providing a supportive environment and letting them explore gender expression with haircut, clothing, toys, name, and pronouns may be the main “interventions.” Ensure a safe bathroom and safe spaces at school (and home), and perhaps find an experienced therapist comfortable navigating gender concerns. Supporting the family supports the child and can make all the difference in the world. Often clinics specializing in gender care will see young children to provide this support and follow the child into puberty.

Nosyrevy/Getty Images

Once puberty starts, however, medical interventions can be discussed and puberty blockers are a great place to start, given their reversibility. Having an understanding of how puberty blockers work, the side effects, and timing of blocker use is important to the average pediatric provider as you may see some of these children and be able to intervene by sending them to a specialist early!
 

How do puberty blockers work?

One of the first hormonal signals of puberty is the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH then stimulate sex steroidogenesis (production of estradiol or testosterone) and gametogenesis in the gonads. The most common choice for puberty blockers are GnRH agonists, such as leuprolide (a series of shots) or histrelin (an implantable rod), which have been studied extensively for the treatment of children with central precocious puberty, and more recently gender dysphoria. Interestingly, these medicines actually stimulate gonadotropin release and the overproduction makes the gonadotropin receptors less sensitive.¹ Gradually the production of sex steroids decreases. One of the advantages of puberty blockers is that they are reversible – stop the medication and the effects wear off, allowing one to proceed with natal puberty if one so desires. Gender specialists always start with the most reversible intervention, especially at such a young age. Puberty blockers are like a pause button that gives everyone – patient, clinicians, therapists – time to process, explore, and ensure transition is the right path.

Sexual development should stop on puberty blockers. For those born with ovaries, breasts will not continue to develop and menses will not start if premenarchal or stop soon if postmenarchal. For those born with testicles, testicular and penile enlargement will not proceed, the voice will not deepen, hands will not grow in size, and an “Adam’s apple” will not develop. Preventing these changes may not only prevent future surgeries (mastectomy, tracheal shaving, etc.) but may also be lifesaving given the lack of development as secondary sex characteristics may not develop, thus avoiding telltale signs that one has transitioned physically, particularly for transwomen.
 

What are the side effects of puberty blockers?

Whenever an adolescent is started on puberty blockers, it is important to discuss both the main effects (i.e., cessation of puberty and sexual development) as well as the side effects. There are four main side effect areas that are important to cover: bone health and height, brain development, fertility, and surgical implications.

• Bone health & height. Adolescence is an important time for growth. During adolescence, bones grow both in length, which determines an individual’s height, and in density, which can affect risk of osteoporosis later on in life. Sex steroids are an important factor for both of these issues. Estradiol is responsible for closure of the growth plates and, in general, those born with ovaries enter puberty earlier than those born with testicles, therefore they see higher rates of estradiol earlier, which causes cessation of growth, hence why females are typically shorter than males. Delaying these high levels of estrogen may give transmales (female to male individuals) more time to grow. Conversely, decreasing release of testosterone in transfemales (male to female individuals) and then introducing estradiol at higher levels earlier than they would experience with their natal puberty may stop transfemales from growing much taller than the average cisgender woman. Bone density also is a major concern as the sex steroids are very important for bone mass accretion.^1,2 Studies in transgender individuals using dual-energy x-ray absorptiometry show that, for transmale patients, z scores do decrease but they tend to catch up once gender-affirming hormones are started. For transfemale patients, the z scores don’t decrease as much but also don’t increase as much once estrogen is started.^1,3 It is for these reasons that the Endocrine Society guidelines recommend monitoring bone density both before and while on puberty blockers.^4,5
• Brain development. Adolescence also is an important time for brain development, particularly the areas that focus on executive function. Studies comparing transgender patients on GnRH agonists noted no detrimental effects on higher-order cognitive process associated with a specific task meant to test executive function.⁶ Although not performed on transgender individuals, a study examining girls with central precocious puberty on GnRH agonists found no difference with the control group on auditory and visual memory, response inhibition, spatial ability, behavioral problems, or social competence.⁷
• Fertility. Suspending puberty at an early Sexual Maturity Rating (such as stage 2 or 3) may make it difficult to harvest mature oocytes or spermatozoa, thus compromising long-term fertility, especially once they start on gender-affirming hormones. While some patients may choose to delay starting puberty blockers for the sake of cryopreservation, others may be in too much distress at their pubertal changes to wait. Fertility counseling is thus an important aspect of the discussion with transgender patients considering puberty blockers and/or gender-affirming hormones.
• Surgical implications. The most common “bottom surgery” performed in transfemales is called penile inversion vaginoplasty, which uses the penile and scrotal skin to create a neovagina.⁸ However, one has to have enough penile and scrotal development for this surgery to be successful, which may mean waiting until a patient has reached Sexual Maturity Rating stage 4 before starting blockers. There are alternative surgical options, but one must discuss the risks and benefits of waiting to start blockers with the patient and family.

When can puberty blockers be started?

Patients must meet criteria for gender dysphoria with emergence or worsening with puberty.⁹ Any coexisting conditions (psychological, medical, social) that could interfere with treatment have to be addressed, and both the patient and their guardian must undergo informed consent for treatment.^4,5,10 Puberty blockers cannot be used until after puberty has started, so at least Sexual Maturity Rating stage 2. In the early stages of puberty, hormonally one will see LH rise followed by rise in estradiol and/or testosterone. Consideration for both the development of secondary sex characteristics and associated increased distress or dysphoria as well as surgical implications must be weighed in each individual case. The bottom line is that these medications can be life saving and are reversible, so if a patient and/or family decides to stop them, the effects will wear off and natal puberty will resume.

Dr. Lawlis is an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Diabetes Endocrinol. 2017 Oct. doi: 10.1016/S2213-8587(17)30099-2.

2. Bone. 2010 Feb. doi: 10.1016/j.bone.2009.10.005.

3. J Clin Endocrinol Metab. 2015 Feb. doi: 10.1210/jc.2014-2439.

4. J Clin Endocrinol Metab. 2009 Sep. doi: 10.1210/jc.2009-0345.

5. J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658.

6. Psychoneuroendocrinology. 2015 Jun. doi: 10.1016/j.psyneuen.2015.03.007.

7. Front Psychol. 2016 Jul. doi: 10.3389/fpsyg.2016.01053.

8. Sex Med Rev. 2017 Jan. doi: 10.1016/j.sxmr.2016.08.001.

9. “Diagnostic and Statistical Manual of Mental Disorders,” 5th ed. (Arlington, Va.: American Psychiatric Association, 2013).

10. Int J Transgend. 2012. doi: 10.1080/15532739.2011.700873.

While many transgender individuals develop their gender identity early on in life, medically there may not be any intervention until they hit puberty. For prepubertal children, providing a supportive environment and letting them explore gender expression with haircut, clothing, toys, name, and pronouns may be the main “interventions.” Ensure a safe bathroom and safe spaces at school (and home), and perhaps find an experienced therapist comfortable navigating gender concerns. Supporting the family supports the child and can make all the difference in the world. Often clinics specializing in gender care will see young children to provide this support and follow the child into puberty.

Nosyrevy/Getty Images

Once puberty starts, however, medical interventions can be discussed and puberty blockers are a great place to start, given their reversibility. Having an understanding of how puberty blockers work, the side effects, and timing of blocker use is important to the average pediatric provider as you may see some of these children and be able to intervene by sending them to a specialist early!
 

How do puberty blockers work?

One of the first hormonal signals of puberty is the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. LH and FSH then stimulate sex steroidogenesis (production of estradiol or testosterone) and gametogenesis in the gonads. The most common choice for puberty blockers are GnRH agonists, such as leuprolide (a series of shots) or histrelin (an implantable rod), which have been studied extensively for the treatment of children with central precocious puberty, and more recently gender dysphoria. Interestingly, these medicines actually stimulate gonadotropin release and the overproduction makes the gonadotropin receptors less sensitive.¹ Gradually the production of sex steroids decreases. One of the advantages of puberty blockers is that they are reversible – stop the medication and the effects wear off, allowing one to proceed with natal puberty if one so desires. Gender specialists always start with the most reversible intervention, especially at such a young age. Puberty blockers are like a pause button that gives everyone – patient, clinicians, therapists – time to process, explore, and ensure transition is the right path.

Sexual development should stop on puberty blockers. For those born with ovaries, breasts will not continue to develop and menses will not start if premenarchal or stop soon if postmenarchal. For those born with testicles, testicular and penile enlargement will not proceed, the voice will not deepen, hands will not grow in size, and an “Adam’s apple” will not develop. Preventing these changes may not only prevent future surgeries (mastectomy, tracheal shaving, etc.) but may also be lifesaving given the lack of development as secondary sex characteristics may not develop, thus avoiding telltale signs that one has transitioned physically, particularly for transwomen.
 

What are the side effects of puberty blockers?

Whenever an adolescent is started on puberty blockers, it is important to discuss both the main effects (i.e., cessation of puberty and sexual development) as well as the side effects. There are four main side effect areas that are important to cover: bone health and height, brain development, fertility, and surgical implications.

• Bone health & height. Adolescence is an important time for growth. During adolescence, bones grow both in length, which determines an individual’s height, and in density, which can affect risk of osteoporosis later on in life. Sex steroids are an important factor for both of these issues. Estradiol is responsible for closure of the growth plates and, in general, those born with ovaries enter puberty earlier than those born with testicles, therefore they see higher rates of estradiol earlier, which causes cessation of growth, hence why females are typically shorter than males. Delaying these high levels of estrogen may give transmales (female to male individuals) more time to grow. Conversely, decreasing release of testosterone in transfemales (male to female individuals) and then introducing estradiol at higher levels earlier than they would experience with their natal puberty may stop transfemales from growing much taller than the average cisgender woman. Bone density also is a major concern as the sex steroids are very important for bone mass accretion.^1,2 Studies in transgender individuals using dual-energy x-ray absorptiometry show that, for transmale patients, z scores do decrease but they tend to catch up once gender-affirming hormones are started. For transfemale patients, the z scores don’t decrease as much but also don’t increase as much once estrogen is started.^1,3 It is for these reasons that the Endocrine Society guidelines recommend monitoring bone density both before and while on puberty blockers.^4,5
• Brain development. Adolescence also is an important time for brain development, particularly the areas that focus on executive function. Studies comparing transgender patients on GnRH agonists noted no detrimental effects on higher-order cognitive process associated with a specific task meant to test executive function.⁶ Although not performed on transgender individuals, a study examining girls with central precocious puberty on GnRH agonists found no difference with the control group on auditory and visual memory, response inhibition, spatial ability, behavioral problems, or social competence.⁷
• Fertility. Suspending puberty at an early Sexual Maturity Rating (such as stage 2 or 3) may make it difficult to harvest mature oocytes or spermatozoa, thus compromising long-term fertility, especially once they start on gender-affirming hormones. While some patients may choose to delay starting puberty blockers for the sake of cryopreservation, others may be in too much distress at their pubertal changes to wait. Fertility counseling is thus an important aspect of the discussion with transgender patients considering puberty blockers and/or gender-affirming hormones.
• Surgical implications. The most common “bottom surgery” performed in transfemales is called penile inversion vaginoplasty, which uses the penile and scrotal skin to create a neovagina.⁸ However, one has to have enough penile and scrotal development for this surgery to be successful, which may mean waiting until a patient has reached Sexual Maturity Rating stage 4 before starting blockers. There are alternative surgical options, but one must discuss the risks and benefits of waiting to start blockers with the patient and family.

When can puberty blockers be started?

Patients must meet criteria for gender dysphoria with emergence or worsening with puberty.⁹ Any coexisting conditions (psychological, medical, social) that could interfere with treatment have to be addressed, and both the patient and their guardian must undergo informed consent for treatment.^4,5,10 Puberty blockers cannot be used until after puberty has started, so at least Sexual Maturity Rating stage 2. In the early stages of puberty, hormonally one will see LH rise followed by rise in estradiol and/or testosterone. Consideration for both the development of secondary sex characteristics and associated increased distress or dysphoria as well as surgical implications must be weighed in each individual case. The bottom line is that these medications can be life saving and are reversible, so if a patient and/or family decides to stop them, the effects will wear off and natal puberty will resume.

Dr. Lawlis is an assistant professor of pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City, and an adolescent medicine specialist at OU Children’s. She has no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Diabetes Endocrinol. 2017 Oct. doi: 10.1016/S2213-8587(17)30099-2.

2. Bone. 2010 Feb. doi: 10.1016/j.bone.2009.10.005.

3. J Clin Endocrinol Metab. 2015 Feb. doi: 10.1210/jc.2014-2439.

4. J Clin Endocrinol Metab. 2009 Sep. doi: 10.1210/jc.2009-0345.

5. J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658.

6. Psychoneuroendocrinology. 2015 Jun. doi: 10.1016/j.psyneuen.2015.03.007.

7. Front Psychol. 2016 Jul. doi: 10.3389/fpsyg.2016.01053.

8. Sex Med Rev. 2017 Jan. doi: 10.1016/j.sxmr.2016.08.001.

9. “Diagnostic and Statistical Manual of Mental Disorders,” 5th ed. (Arlington, Va.: American Psychiatric Association, 2013).

10. Int J Transgend. 2012. doi: 10.1080/15532739.2011.700873.