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Dangers behind antimaskers and antivaxxers: How to combat both
Niket Sonpal, MD, thought he’d heard most of the myths about wearing masks during the pandemic, but the recent claim from a patient was a new one for the New York City gastroenterologist.
The patient refused to wear a mask because she heard inhaling bad breath through a mask could be toxic. The woman said the rumor was circulating on Facebook. Sonpal calmly explained that breathing your own breath is not going to cause health problems, he said.
“There’s a lot of controversy on masks,” he said. “Unfortunately, it’s really just a lack of education and buy-in. Social media is the primary source of all this misinformation. These kinds of over-the-top hyperbole has basically led to a disbelief that masks are effective. The disbelief is hard to break up.”
As mask requirements have tightened amid the ongoing pandemic, debates about face coverings have emerged front and center, with a growing number of people opposing mask usage. So-called antimaskers dispute the benefits of wearing masks and many contend that face coverings decrease oxygen flow and can lead to illness. Sentiment against masks have led to protests nationwide, ignited public conflicts in some areas, and even generated lawsuits over mask mandates.
The issue presents an ongoing challenge for physicians as they strive to educate patients about the significance of masking against the flood of antimask messages on social media and beyond. Opposition to masks is particularly frustrating for health professionals who have witnessed patients, family, or friends become ill or die from the virus. Refusing to mask and failing to social distance have been linked to the rapid spread of the coronavirus and subsequent deaths.
“I have had colleagues pass away, and it’s extremely disheartening and frustrating to see science so easily disregarded,” Sonpal said. “Masks save lives and protect people and not wearing them is simply a lack of respect, not just for your fellow colleagues, but for a member of your species.”
Michael Rebresh, who helped create the antimask group Million Unmasked Patriots, says his group’s objections to masks are rational and reasonable. The group, which has more than 8,000 members, formed in response to guidance by Illinois state officials that children would only be allowed to return to school wearing a mask.
“Our objections are to the fact that masks on children in school have a greater propensity to make children sick from breathing in bacteria that forms on the inner layer of a mask worn for hours on end,” Rebresh said. “We have an objection to the increase of CO2 intake and a decrease in oxygen flow for kids who need all the oxygen they can get during a learning environment. We recognized the masking of ourselves and kids for what it is: A political move to separate the two parties in our November election and define and create division between the two.”
Million Unmasked Patriots is one of dozens of antimask groups on social media platforms such as Facebook, Instagram, and TikTok. In July, Facebook suspended one such group, Unmasking America, which boasts 9,600 members, for posting repeated claims that face masks obstruct oxygen flow and have negative mental health effects.
Experts say the antiscience rhetoric is far from new. The antimask movement in many ways, shares similarities with that of the anti-vaccine movement, says Todd Wolynn, MD, a Pittsburgh pediatrician and cofounder of Shots Heard Round the World, an organization that defends vaccine advocates against coordinated online attacks by antivaxxers.
“A lot of it is conspiracy-laden,” said Wolynn of the disinformation. “That Dr. [Anthony] Fauci somehow helped construct the pandemic and that it’s not real. That Bill Gates is funding the vaccine so he can inject people with microchips. All sorts of really out-there, ungrounded conspiracy theories. If you had Venn diagram of antimask and antivaxx, I would say there’s clearly overlap.”
Parallels between antimaskers, antivaxxers
Opponents to masks fall on a spectrum, explains Vineet Arora, MD, a hospitalist and associate chief medical officer–clinical learning environment at University of Chicago Medicine. People who believe conspiracy theories and push misinformation are on one end, she said. There are also those who generally don’t believe the seriousness of the pandemic, feel their risk is minimal, or doubt the benefits of masks.
The two trains of thought resemble the distinction among parents who are antivaccine and those who are simply “vaccine hesitant,” says Arora, who co-authored a recent article about masking and misinformation that addresses antivaccine attitudes.
“While the antimask sentiment gets a lot of attention, I think it’s important to highlight there’s a lot of vocal anti-mask sentiment since most people are supportive of masks,” she said. “There might be people sitting on the fence who are just unsure about wearing a mask. That’s understandable because the science and the communication has evolved. There was a lot of early mixed messages about masking. Anytime you have confusion about the science or the science is evolving, it’s easy to have misinformation and then have that take off as myth.”
Just as antivaxxers work to swing the opinion of the vaccine hesitant, antimaskers are vying with public health advocates for the support of the mask hesitant, she said. Creating doubt in public health authorities is one way they are gaining followers. Anti-maskers often question and scrutinize past messaging about masks by public health officials, claiming that because guidance on masks has changed over time, the science behind masks and current guidance can’t be trusted, Wolynn said. Similarly, antivaxxers frequently question past actions by public health officials, such as the Tuskegee Experiment (which began in 1932), to try to poke holes in the credibility of public health officials and their advice.
Both the antimask and antivaccine movements also tend to base their resistance on a personal liberties argument, adds Jacqueline Winfield Fincher, MD, president for the American College of Physicians and an internist based in Thomson, Georgia. Antimaskers contend they should be free to decide whether to wear face coverings and that rules requiring masks infringe upon their civil liberties. Similarly, antivaxxers argue they should be free to decide whether to vaccinate their children and contend vaccine mandates violate their personal liberties.
Taking a deeper look, fear and control are two likely drivers of antimasking and antivaccine attitudes, Fincher said. Those refusing to wear masks may feel they have no control over the pandemic or its impacts, but they can control how they respond to mask-wearing requirements, she said.
Antivaccine parents often want more control over their children’s healthcare and falsely believe that vaccines are injecting something harmful into their children or may lead to harmful reactions.
“It’s a control issue and a defense mechanism,” she said. “Some people may feel helpless to deal with the pandemic or believe since it is not affecting them or their family, that it is not real. ‘If I just deny it and I don’t acknowledge facts, I don’t have to worry about it or do anything about it, and therefore I will have more control over my day-to-day life.’”
Groups fueling each other
In some cases, antimask and antivaxx groups are joining forces or adopting dual causes.
In California for instance, longtime opponents to vaccines are now objecting to mask policies as similar infringement to their bodily autonomy. Demonstrations in Texas, Idaho, and Michigan against mask mandates and other COVID-19 requirements have drawn support from anti-vaccine activists and incorporated antivaccine propaganda.
In Illinois, Million Unmasked Patriots, formally the Million Unmasked March, has received widespread attention for protesting both masks for returning schoolchildren and a future COVID-19 vaccine requirement.
A July protest planned by the antimask group triggered a letter by Arora and 500 other healthcare professionals to Illinois lawmakers decrying the group’s views and urging the state to move forward with universal masking in schools.
“What’s happening is those who are distrustful of government and public health and science are joining together,” said Arora, who coauthored a piece about the problem on KevinMD.com. “It’s important to address both movements together because they can quickly feed off each other and build in momentum. At the heart of both is really this deep skepticism of science.”
Rebresh of Million Unmasked Patriots said most of his members are not opposed to all vaccines, but rather they are opposed to “untested vaccines.” The primary concern is the inability to research long-term effects of a COVID-19 vaccine before its approval, he said.
Rebresh disagrees with the antimask movement being compared with the antivaccine movement. The two groups are “motivated by different things and a different set of circumstances drive their opinions,” he said. However, Rebresh believes that potential harm resulting from “mass vaccinations” is a valid concern. For this reason, he and his wife chose for their children to receive their vaccinations individually over a series of weeks, rather than the “kiddie cocktail of vaccines,” at a single visit, he said.
Vaccine scientist Peter Hotez, MD, PhD, said the antivaccine movement appears to have grown stronger from the pandemic fueled by fresh conspiracies and new alliances. Antivaccine sentiment has been gaining steam over the last several years and collecting more allies from the far-right, said Hotez, dean for the National School of Tropical Medicine and codirector for the Texas Children’s Hospital Center for Vaccine Development.
“Now what you’re seeing is yet another expansion this year, with antivaccine groups, under the banner of ‘health freedom,’ campaigning against social distancing and wearing masks and contact tracing,” he said. “What was an antivaccine movement has now become a full-blown antiscience movement and an anti-public health movement. It’s causing a lot of damage and I believe costing a lot of American lives.”
Neil F. Johnson, PhD, who has studied the antivaccine movement and its social media proliferation during the pandemic, said online comments by antivaxxers frequently condemn mask usage and showcase memes making fun of masks.
“In those same narratives about opposing vaccines for COVID, we see a lot of discussion against masks,” said Johnson, a physics professor at George Washington University in Washington, D.C. “If you don’t believe in the official picture of COVID, you don’t believe the policies or the advice that’s given about COVID.”
An analysis by Johnson that examined 1,300 Facebook pages found that, while antivaxxers have fewer followers than provaccine pages, antivaccine pages are more numerous, faster growing, and are more often connected to unrelated, undecided pages. Conversely, pages that advocate the benefits of vaccinations and explain the science behind immunizations are largely disconnected from such undecided communities, according to the study, published May 13 in Nature.
The study suggests the antivaccine movement is making influential strides during the pandemic and connecting with people who are undecided, while public health advocates are not building the same bridges, Johnson said.
“I think it’s hugely dangerous, because I don’t know any other moment in science or in public health when there was so much uncertainty in something affecting everybody,” he said. “Every policy that will be coming, everything depends on people buying into the official message. Once you have the seeds of doubt, that’s a very difficult thing to overcome. It’s an unprecedented challenge.”
How physicians and clinicians can help
A more aggressive approach is necessary when it comes to taking down antiscience content on social media, says Hotez. Too often, misinformation and antiscience rhetoric is allowed to linger on popular sites such as Facebook and Amazon.
Wolynn agrees. On personal or business platforms, it’s crucial to ban, hide, and delete such comments as quickly as possible, he said. On public sites, purposeful disinformation should be immediately reported to the platform.
At the same time, Wolynn said it’s essential to support those who make sound, science-based comments in social media forums.
“If you see someone who is pushing accurate, evidence-based information, and they come under attack, they should be supported and defended and empowered,” Wolynn said. “Shots Heard Round the World is doing all of those things, including galvanizing and recruiting more people to help get their voices out there.”
Expanded visibility by physicians and scientists would greatly help counter the spread of antiscience sentiment, adds Hotez.
“Too often, antiscience movements are able to flourish because scientists and physicians are invisible,” he said. “They’re too focused on either clinical practices or in the case of physician scientists, on grants and papers and not enough attention to public engagement. We’re going to have to change that around. We need to hear more from scientists directly.”
To that end, Wolynn said health care professionals, including medical students and residents, need to have formal training in communications, media, and social media as part of their education – and more support from employers to engage through social media.
“That’s where the fight is,” Wolynn said. “You can be the best diagnostician, the best clinician. You can make the right diagnosis and prescribe the right medication, but if families don’t hear what you’re saying, you’re not going to be effective. If you can’t be on the platform where they’re being influenced, we’re losing the battle.”
Speaking to your mask-hesitant patients
Concentrating on those who are uncertain about masks is particularly key for physicians and public health advocates as the pandemic continues, says Arora.
“It’s important for us to focus on the mask-hesitant who often don’t get the attention they need,” she said.
She suggests bringing up the subject of masks with patients during visits, asking about mask usage, discussing rumors they’ve heard, and emphasizing why masks are important. Be a role model by wearing a mask in your community and on social media, she added.
Some patients have real concerns about not being able to breathe through masks or anxiety disorders that can be aggravated even by the thought of wearing a mask, noted Susan R. Bailey, MD, president for the American Medical Association. Bailey, an immunologist, recently counseled a patient with a deviated nasal septum in addition to a panic disorder who was worried about wearing a mask, she said. Bailey listened to the patient’s concerns, discussed his health conditions, and proposed an alternative face covering that might make him more comfortable.
“Every patient is different,” Bailey said. “It’s important for us to remember that each person who is reluctant to wear a mask has their own reasons. It’s important for us to express some empathy – to agree with them, yes, masks are hot and inconvenient – and help understand their questions, which you may be able to answer to their satisfaction. There are patients that have legitimate questions and a physician caring about how they feel, can make all the difference.”
Physicians can also get involved with the AMA’s #MaskUp campaign, an effort to normalize mask wearing and debunk myths associated with masks. The campaign includes social media materials, slogans doctors can tweet, and profile pictures they can use on social media. The campaign’s toolkit includes images, videos, and information that physicians can share with patients and the public.
Enforcing strong mask policies at your practice and ensuring all staff are modeling appropriate mask behavior is also important, adds Fincher of the ACP. The college recently issued a policy supporting mask usage in community settings.
If a patient conveys an antimask belief, Fincher suggests not directly challenging the person’s views, but listening to them and offering objective data, discussing the science behind masks, and directing them to credible sources.
“Doctors are used to this. We recommend a lot of things to patients that they don’t want to do,” Fincher said. “If a patient feels attacked, they act defensively. But if you base your explanation in more objective terms with data, numbers, and personalize the risks and benefits of a vaccine, a healthy change in behavior, or a medication, then patients are more likely to hear your concerns and do the right thing. Having a long-term relationship with a trusted physician makes all of these issues much easier to discuss and to implement the best plan for the individual patient.”
This article first appeared on Medscape.com.
Niket Sonpal, MD, thought he’d heard most of the myths about wearing masks during the pandemic, but the recent claim from a patient was a new one for the New York City gastroenterologist.
The patient refused to wear a mask because she heard inhaling bad breath through a mask could be toxic. The woman said the rumor was circulating on Facebook. Sonpal calmly explained that breathing your own breath is not going to cause health problems, he said.
“There’s a lot of controversy on masks,” he said. “Unfortunately, it’s really just a lack of education and buy-in. Social media is the primary source of all this misinformation. These kinds of over-the-top hyperbole has basically led to a disbelief that masks are effective. The disbelief is hard to break up.”
As mask requirements have tightened amid the ongoing pandemic, debates about face coverings have emerged front and center, with a growing number of people opposing mask usage. So-called antimaskers dispute the benefits of wearing masks and many contend that face coverings decrease oxygen flow and can lead to illness. Sentiment against masks have led to protests nationwide, ignited public conflicts in some areas, and even generated lawsuits over mask mandates.
The issue presents an ongoing challenge for physicians as they strive to educate patients about the significance of masking against the flood of antimask messages on social media and beyond. Opposition to masks is particularly frustrating for health professionals who have witnessed patients, family, or friends become ill or die from the virus. Refusing to mask and failing to social distance have been linked to the rapid spread of the coronavirus and subsequent deaths.
“I have had colleagues pass away, and it’s extremely disheartening and frustrating to see science so easily disregarded,” Sonpal said. “Masks save lives and protect people and not wearing them is simply a lack of respect, not just for your fellow colleagues, but for a member of your species.”
Michael Rebresh, who helped create the antimask group Million Unmasked Patriots, says his group’s objections to masks are rational and reasonable. The group, which has more than 8,000 members, formed in response to guidance by Illinois state officials that children would only be allowed to return to school wearing a mask.
“Our objections are to the fact that masks on children in school have a greater propensity to make children sick from breathing in bacteria that forms on the inner layer of a mask worn for hours on end,” Rebresh said. “We have an objection to the increase of CO2 intake and a decrease in oxygen flow for kids who need all the oxygen they can get during a learning environment. We recognized the masking of ourselves and kids for what it is: A political move to separate the two parties in our November election and define and create division between the two.”
Million Unmasked Patriots is one of dozens of antimask groups on social media platforms such as Facebook, Instagram, and TikTok. In July, Facebook suspended one such group, Unmasking America, which boasts 9,600 members, for posting repeated claims that face masks obstruct oxygen flow and have negative mental health effects.
Experts say the antiscience rhetoric is far from new. The antimask movement in many ways, shares similarities with that of the anti-vaccine movement, says Todd Wolynn, MD, a Pittsburgh pediatrician and cofounder of Shots Heard Round the World, an organization that defends vaccine advocates against coordinated online attacks by antivaxxers.
“A lot of it is conspiracy-laden,” said Wolynn of the disinformation. “That Dr. [Anthony] Fauci somehow helped construct the pandemic and that it’s not real. That Bill Gates is funding the vaccine so he can inject people with microchips. All sorts of really out-there, ungrounded conspiracy theories. If you had Venn diagram of antimask and antivaxx, I would say there’s clearly overlap.”
Parallels between antimaskers, antivaxxers
Opponents to masks fall on a spectrum, explains Vineet Arora, MD, a hospitalist and associate chief medical officer–clinical learning environment at University of Chicago Medicine. People who believe conspiracy theories and push misinformation are on one end, she said. There are also those who generally don’t believe the seriousness of the pandemic, feel their risk is minimal, or doubt the benefits of masks.
The two trains of thought resemble the distinction among parents who are antivaccine and those who are simply “vaccine hesitant,” says Arora, who co-authored a recent article about masking and misinformation that addresses antivaccine attitudes.
“While the antimask sentiment gets a lot of attention, I think it’s important to highlight there’s a lot of vocal anti-mask sentiment since most people are supportive of masks,” she said. “There might be people sitting on the fence who are just unsure about wearing a mask. That’s understandable because the science and the communication has evolved. There was a lot of early mixed messages about masking. Anytime you have confusion about the science or the science is evolving, it’s easy to have misinformation and then have that take off as myth.”
Just as antivaxxers work to swing the opinion of the vaccine hesitant, antimaskers are vying with public health advocates for the support of the mask hesitant, she said. Creating doubt in public health authorities is one way they are gaining followers. Anti-maskers often question and scrutinize past messaging about masks by public health officials, claiming that because guidance on masks has changed over time, the science behind masks and current guidance can’t be trusted, Wolynn said. Similarly, antivaxxers frequently question past actions by public health officials, such as the Tuskegee Experiment (which began in 1932), to try to poke holes in the credibility of public health officials and their advice.
Both the antimask and antivaccine movements also tend to base their resistance on a personal liberties argument, adds Jacqueline Winfield Fincher, MD, president for the American College of Physicians and an internist based in Thomson, Georgia. Antimaskers contend they should be free to decide whether to wear face coverings and that rules requiring masks infringe upon their civil liberties. Similarly, antivaxxers argue they should be free to decide whether to vaccinate their children and contend vaccine mandates violate their personal liberties.
Taking a deeper look, fear and control are two likely drivers of antimasking and antivaccine attitudes, Fincher said. Those refusing to wear masks may feel they have no control over the pandemic or its impacts, but they can control how they respond to mask-wearing requirements, she said.
Antivaccine parents often want more control over their children’s healthcare and falsely believe that vaccines are injecting something harmful into their children or may lead to harmful reactions.
“It’s a control issue and a defense mechanism,” she said. “Some people may feel helpless to deal with the pandemic or believe since it is not affecting them or their family, that it is not real. ‘If I just deny it and I don’t acknowledge facts, I don’t have to worry about it or do anything about it, and therefore I will have more control over my day-to-day life.’”
Groups fueling each other
In some cases, antimask and antivaxx groups are joining forces or adopting dual causes.
In California for instance, longtime opponents to vaccines are now objecting to mask policies as similar infringement to their bodily autonomy. Demonstrations in Texas, Idaho, and Michigan against mask mandates and other COVID-19 requirements have drawn support from anti-vaccine activists and incorporated antivaccine propaganda.
In Illinois, Million Unmasked Patriots, formally the Million Unmasked March, has received widespread attention for protesting both masks for returning schoolchildren and a future COVID-19 vaccine requirement.
A July protest planned by the antimask group triggered a letter by Arora and 500 other healthcare professionals to Illinois lawmakers decrying the group’s views and urging the state to move forward with universal masking in schools.
“What’s happening is those who are distrustful of government and public health and science are joining together,” said Arora, who coauthored a piece about the problem on KevinMD.com. “It’s important to address both movements together because they can quickly feed off each other and build in momentum. At the heart of both is really this deep skepticism of science.”
Rebresh of Million Unmasked Patriots said most of his members are not opposed to all vaccines, but rather they are opposed to “untested vaccines.” The primary concern is the inability to research long-term effects of a COVID-19 vaccine before its approval, he said.
Rebresh disagrees with the antimask movement being compared with the antivaccine movement. The two groups are “motivated by different things and a different set of circumstances drive their opinions,” he said. However, Rebresh believes that potential harm resulting from “mass vaccinations” is a valid concern. For this reason, he and his wife chose for their children to receive their vaccinations individually over a series of weeks, rather than the “kiddie cocktail of vaccines,” at a single visit, he said.
Vaccine scientist Peter Hotez, MD, PhD, said the antivaccine movement appears to have grown stronger from the pandemic fueled by fresh conspiracies and new alliances. Antivaccine sentiment has been gaining steam over the last several years and collecting more allies from the far-right, said Hotez, dean for the National School of Tropical Medicine and codirector for the Texas Children’s Hospital Center for Vaccine Development.
“Now what you’re seeing is yet another expansion this year, with antivaccine groups, under the banner of ‘health freedom,’ campaigning against social distancing and wearing masks and contact tracing,” he said. “What was an antivaccine movement has now become a full-blown antiscience movement and an anti-public health movement. It’s causing a lot of damage and I believe costing a lot of American lives.”
Neil F. Johnson, PhD, who has studied the antivaccine movement and its social media proliferation during the pandemic, said online comments by antivaxxers frequently condemn mask usage and showcase memes making fun of masks.
“In those same narratives about opposing vaccines for COVID, we see a lot of discussion against masks,” said Johnson, a physics professor at George Washington University in Washington, D.C. “If you don’t believe in the official picture of COVID, you don’t believe the policies or the advice that’s given about COVID.”
An analysis by Johnson that examined 1,300 Facebook pages found that, while antivaxxers have fewer followers than provaccine pages, antivaccine pages are more numerous, faster growing, and are more often connected to unrelated, undecided pages. Conversely, pages that advocate the benefits of vaccinations and explain the science behind immunizations are largely disconnected from such undecided communities, according to the study, published May 13 in Nature.
The study suggests the antivaccine movement is making influential strides during the pandemic and connecting with people who are undecided, while public health advocates are not building the same bridges, Johnson said.
“I think it’s hugely dangerous, because I don’t know any other moment in science or in public health when there was so much uncertainty in something affecting everybody,” he said. “Every policy that will be coming, everything depends on people buying into the official message. Once you have the seeds of doubt, that’s a very difficult thing to overcome. It’s an unprecedented challenge.”
How physicians and clinicians can help
A more aggressive approach is necessary when it comes to taking down antiscience content on social media, says Hotez. Too often, misinformation and antiscience rhetoric is allowed to linger on popular sites such as Facebook and Amazon.
Wolynn agrees. On personal or business platforms, it’s crucial to ban, hide, and delete such comments as quickly as possible, he said. On public sites, purposeful disinformation should be immediately reported to the platform.
At the same time, Wolynn said it’s essential to support those who make sound, science-based comments in social media forums.
“If you see someone who is pushing accurate, evidence-based information, and they come under attack, they should be supported and defended and empowered,” Wolynn said. “Shots Heard Round the World is doing all of those things, including galvanizing and recruiting more people to help get their voices out there.”
Expanded visibility by physicians and scientists would greatly help counter the spread of antiscience sentiment, adds Hotez.
“Too often, antiscience movements are able to flourish because scientists and physicians are invisible,” he said. “They’re too focused on either clinical practices or in the case of physician scientists, on grants and papers and not enough attention to public engagement. We’re going to have to change that around. We need to hear more from scientists directly.”
To that end, Wolynn said health care professionals, including medical students and residents, need to have formal training in communications, media, and social media as part of their education – and more support from employers to engage through social media.
“That’s where the fight is,” Wolynn said. “You can be the best diagnostician, the best clinician. You can make the right diagnosis and prescribe the right medication, but if families don’t hear what you’re saying, you’re not going to be effective. If you can’t be on the platform where they’re being influenced, we’re losing the battle.”
Speaking to your mask-hesitant patients
Concentrating on those who are uncertain about masks is particularly key for physicians and public health advocates as the pandemic continues, says Arora.
“It’s important for us to focus on the mask-hesitant who often don’t get the attention they need,” she said.
She suggests bringing up the subject of masks with patients during visits, asking about mask usage, discussing rumors they’ve heard, and emphasizing why masks are important. Be a role model by wearing a mask in your community and on social media, she added.
Some patients have real concerns about not being able to breathe through masks or anxiety disorders that can be aggravated even by the thought of wearing a mask, noted Susan R. Bailey, MD, president for the American Medical Association. Bailey, an immunologist, recently counseled a patient with a deviated nasal septum in addition to a panic disorder who was worried about wearing a mask, she said. Bailey listened to the patient’s concerns, discussed his health conditions, and proposed an alternative face covering that might make him more comfortable.
“Every patient is different,” Bailey said. “It’s important for us to remember that each person who is reluctant to wear a mask has their own reasons. It’s important for us to express some empathy – to agree with them, yes, masks are hot and inconvenient – and help understand their questions, which you may be able to answer to their satisfaction. There are patients that have legitimate questions and a physician caring about how they feel, can make all the difference.”
Physicians can also get involved with the AMA’s #MaskUp campaign, an effort to normalize mask wearing and debunk myths associated with masks. The campaign includes social media materials, slogans doctors can tweet, and profile pictures they can use on social media. The campaign’s toolkit includes images, videos, and information that physicians can share with patients and the public.
Enforcing strong mask policies at your practice and ensuring all staff are modeling appropriate mask behavior is also important, adds Fincher of the ACP. The college recently issued a policy supporting mask usage in community settings.
If a patient conveys an antimask belief, Fincher suggests not directly challenging the person’s views, but listening to them and offering objective data, discussing the science behind masks, and directing them to credible sources.
“Doctors are used to this. We recommend a lot of things to patients that they don’t want to do,” Fincher said. “If a patient feels attacked, they act defensively. But if you base your explanation in more objective terms with data, numbers, and personalize the risks and benefits of a vaccine, a healthy change in behavior, or a medication, then patients are more likely to hear your concerns and do the right thing. Having a long-term relationship with a trusted physician makes all of these issues much easier to discuss and to implement the best plan for the individual patient.”
This article first appeared on Medscape.com.
Niket Sonpal, MD, thought he’d heard most of the myths about wearing masks during the pandemic, but the recent claim from a patient was a new one for the New York City gastroenterologist.
The patient refused to wear a mask because she heard inhaling bad breath through a mask could be toxic. The woman said the rumor was circulating on Facebook. Sonpal calmly explained that breathing your own breath is not going to cause health problems, he said.
“There’s a lot of controversy on masks,” he said. “Unfortunately, it’s really just a lack of education and buy-in. Social media is the primary source of all this misinformation. These kinds of over-the-top hyperbole has basically led to a disbelief that masks are effective. The disbelief is hard to break up.”
As mask requirements have tightened amid the ongoing pandemic, debates about face coverings have emerged front and center, with a growing number of people opposing mask usage. So-called antimaskers dispute the benefits of wearing masks and many contend that face coverings decrease oxygen flow and can lead to illness. Sentiment against masks have led to protests nationwide, ignited public conflicts in some areas, and even generated lawsuits over mask mandates.
The issue presents an ongoing challenge for physicians as they strive to educate patients about the significance of masking against the flood of antimask messages on social media and beyond. Opposition to masks is particularly frustrating for health professionals who have witnessed patients, family, or friends become ill or die from the virus. Refusing to mask and failing to social distance have been linked to the rapid spread of the coronavirus and subsequent deaths.
“I have had colleagues pass away, and it’s extremely disheartening and frustrating to see science so easily disregarded,” Sonpal said. “Masks save lives and protect people and not wearing them is simply a lack of respect, not just for your fellow colleagues, but for a member of your species.”
Michael Rebresh, who helped create the antimask group Million Unmasked Patriots, says his group’s objections to masks are rational and reasonable. The group, which has more than 8,000 members, formed in response to guidance by Illinois state officials that children would only be allowed to return to school wearing a mask.
“Our objections are to the fact that masks on children in school have a greater propensity to make children sick from breathing in bacteria that forms on the inner layer of a mask worn for hours on end,” Rebresh said. “We have an objection to the increase of CO2 intake and a decrease in oxygen flow for kids who need all the oxygen they can get during a learning environment. We recognized the masking of ourselves and kids for what it is: A political move to separate the two parties in our November election and define and create division between the two.”
Million Unmasked Patriots is one of dozens of antimask groups on social media platforms such as Facebook, Instagram, and TikTok. In July, Facebook suspended one such group, Unmasking America, which boasts 9,600 members, for posting repeated claims that face masks obstruct oxygen flow and have negative mental health effects.
Experts say the antiscience rhetoric is far from new. The antimask movement in many ways, shares similarities with that of the anti-vaccine movement, says Todd Wolynn, MD, a Pittsburgh pediatrician and cofounder of Shots Heard Round the World, an organization that defends vaccine advocates against coordinated online attacks by antivaxxers.
“A lot of it is conspiracy-laden,” said Wolynn of the disinformation. “That Dr. [Anthony] Fauci somehow helped construct the pandemic and that it’s not real. That Bill Gates is funding the vaccine so he can inject people with microchips. All sorts of really out-there, ungrounded conspiracy theories. If you had Venn diagram of antimask and antivaxx, I would say there’s clearly overlap.”
Parallels between antimaskers, antivaxxers
Opponents to masks fall on a spectrum, explains Vineet Arora, MD, a hospitalist and associate chief medical officer–clinical learning environment at University of Chicago Medicine. People who believe conspiracy theories and push misinformation are on one end, she said. There are also those who generally don’t believe the seriousness of the pandemic, feel their risk is minimal, or doubt the benefits of masks.
The two trains of thought resemble the distinction among parents who are antivaccine and those who are simply “vaccine hesitant,” says Arora, who co-authored a recent article about masking and misinformation that addresses antivaccine attitudes.
“While the antimask sentiment gets a lot of attention, I think it’s important to highlight there’s a lot of vocal anti-mask sentiment since most people are supportive of masks,” she said. “There might be people sitting on the fence who are just unsure about wearing a mask. That’s understandable because the science and the communication has evolved. There was a lot of early mixed messages about masking. Anytime you have confusion about the science or the science is evolving, it’s easy to have misinformation and then have that take off as myth.”
Just as antivaxxers work to swing the opinion of the vaccine hesitant, antimaskers are vying with public health advocates for the support of the mask hesitant, she said. Creating doubt in public health authorities is one way they are gaining followers. Anti-maskers often question and scrutinize past messaging about masks by public health officials, claiming that because guidance on masks has changed over time, the science behind masks and current guidance can’t be trusted, Wolynn said. Similarly, antivaxxers frequently question past actions by public health officials, such as the Tuskegee Experiment (which began in 1932), to try to poke holes in the credibility of public health officials and their advice.
Both the antimask and antivaccine movements also tend to base their resistance on a personal liberties argument, adds Jacqueline Winfield Fincher, MD, president for the American College of Physicians and an internist based in Thomson, Georgia. Antimaskers contend they should be free to decide whether to wear face coverings and that rules requiring masks infringe upon their civil liberties. Similarly, antivaxxers argue they should be free to decide whether to vaccinate their children and contend vaccine mandates violate their personal liberties.
Taking a deeper look, fear and control are two likely drivers of antimasking and antivaccine attitudes, Fincher said. Those refusing to wear masks may feel they have no control over the pandemic or its impacts, but they can control how they respond to mask-wearing requirements, she said.
Antivaccine parents often want more control over their children’s healthcare and falsely believe that vaccines are injecting something harmful into their children or may lead to harmful reactions.
“It’s a control issue and a defense mechanism,” she said. “Some people may feel helpless to deal with the pandemic or believe since it is not affecting them or their family, that it is not real. ‘If I just deny it and I don’t acknowledge facts, I don’t have to worry about it or do anything about it, and therefore I will have more control over my day-to-day life.’”
Groups fueling each other
In some cases, antimask and antivaxx groups are joining forces or adopting dual causes.
In California for instance, longtime opponents to vaccines are now objecting to mask policies as similar infringement to their bodily autonomy. Demonstrations in Texas, Idaho, and Michigan against mask mandates and other COVID-19 requirements have drawn support from anti-vaccine activists and incorporated antivaccine propaganda.
In Illinois, Million Unmasked Patriots, formally the Million Unmasked March, has received widespread attention for protesting both masks for returning schoolchildren and a future COVID-19 vaccine requirement.
A July protest planned by the antimask group triggered a letter by Arora and 500 other healthcare professionals to Illinois lawmakers decrying the group’s views and urging the state to move forward with universal masking in schools.
“What’s happening is those who are distrustful of government and public health and science are joining together,” said Arora, who coauthored a piece about the problem on KevinMD.com. “It’s important to address both movements together because they can quickly feed off each other and build in momentum. At the heart of both is really this deep skepticism of science.”
Rebresh of Million Unmasked Patriots said most of his members are not opposed to all vaccines, but rather they are opposed to “untested vaccines.” The primary concern is the inability to research long-term effects of a COVID-19 vaccine before its approval, he said.
Rebresh disagrees with the antimask movement being compared with the antivaccine movement. The two groups are “motivated by different things and a different set of circumstances drive their opinions,” he said. However, Rebresh believes that potential harm resulting from “mass vaccinations” is a valid concern. For this reason, he and his wife chose for their children to receive their vaccinations individually over a series of weeks, rather than the “kiddie cocktail of vaccines,” at a single visit, he said.
Vaccine scientist Peter Hotez, MD, PhD, said the antivaccine movement appears to have grown stronger from the pandemic fueled by fresh conspiracies and new alliances. Antivaccine sentiment has been gaining steam over the last several years and collecting more allies from the far-right, said Hotez, dean for the National School of Tropical Medicine and codirector for the Texas Children’s Hospital Center for Vaccine Development.
“Now what you’re seeing is yet another expansion this year, with antivaccine groups, under the banner of ‘health freedom,’ campaigning against social distancing and wearing masks and contact tracing,” he said. “What was an antivaccine movement has now become a full-blown antiscience movement and an anti-public health movement. It’s causing a lot of damage and I believe costing a lot of American lives.”
Neil F. Johnson, PhD, who has studied the antivaccine movement and its social media proliferation during the pandemic, said online comments by antivaxxers frequently condemn mask usage and showcase memes making fun of masks.
“In those same narratives about opposing vaccines for COVID, we see a lot of discussion against masks,” said Johnson, a physics professor at George Washington University in Washington, D.C. “If you don’t believe in the official picture of COVID, you don’t believe the policies or the advice that’s given about COVID.”
An analysis by Johnson that examined 1,300 Facebook pages found that, while antivaxxers have fewer followers than provaccine pages, antivaccine pages are more numerous, faster growing, and are more often connected to unrelated, undecided pages. Conversely, pages that advocate the benefits of vaccinations and explain the science behind immunizations are largely disconnected from such undecided communities, according to the study, published May 13 in Nature.
The study suggests the antivaccine movement is making influential strides during the pandemic and connecting with people who are undecided, while public health advocates are not building the same bridges, Johnson said.
“I think it’s hugely dangerous, because I don’t know any other moment in science or in public health when there was so much uncertainty in something affecting everybody,” he said. “Every policy that will be coming, everything depends on people buying into the official message. Once you have the seeds of doubt, that’s a very difficult thing to overcome. It’s an unprecedented challenge.”
How physicians and clinicians can help
A more aggressive approach is necessary when it comes to taking down antiscience content on social media, says Hotez. Too often, misinformation and antiscience rhetoric is allowed to linger on popular sites such as Facebook and Amazon.
Wolynn agrees. On personal or business platforms, it’s crucial to ban, hide, and delete such comments as quickly as possible, he said. On public sites, purposeful disinformation should be immediately reported to the platform.
At the same time, Wolynn said it’s essential to support those who make sound, science-based comments in social media forums.
“If you see someone who is pushing accurate, evidence-based information, and they come under attack, they should be supported and defended and empowered,” Wolynn said. “Shots Heard Round the World is doing all of those things, including galvanizing and recruiting more people to help get their voices out there.”
Expanded visibility by physicians and scientists would greatly help counter the spread of antiscience sentiment, adds Hotez.
“Too often, antiscience movements are able to flourish because scientists and physicians are invisible,” he said. “They’re too focused on either clinical practices or in the case of physician scientists, on grants and papers and not enough attention to public engagement. We’re going to have to change that around. We need to hear more from scientists directly.”
To that end, Wolynn said health care professionals, including medical students and residents, need to have formal training in communications, media, and social media as part of their education – and more support from employers to engage through social media.
“That’s where the fight is,” Wolynn said. “You can be the best diagnostician, the best clinician. You can make the right diagnosis and prescribe the right medication, but if families don’t hear what you’re saying, you’re not going to be effective. If you can’t be on the platform where they’re being influenced, we’re losing the battle.”
Speaking to your mask-hesitant patients
Concentrating on those who are uncertain about masks is particularly key for physicians and public health advocates as the pandemic continues, says Arora.
“It’s important for us to focus on the mask-hesitant who often don’t get the attention they need,” she said.
She suggests bringing up the subject of masks with patients during visits, asking about mask usage, discussing rumors they’ve heard, and emphasizing why masks are important. Be a role model by wearing a mask in your community and on social media, she added.
Some patients have real concerns about not being able to breathe through masks or anxiety disorders that can be aggravated even by the thought of wearing a mask, noted Susan R. Bailey, MD, president for the American Medical Association. Bailey, an immunologist, recently counseled a patient with a deviated nasal septum in addition to a panic disorder who was worried about wearing a mask, she said. Bailey listened to the patient’s concerns, discussed his health conditions, and proposed an alternative face covering that might make him more comfortable.
“Every patient is different,” Bailey said. “It’s important for us to remember that each person who is reluctant to wear a mask has their own reasons. It’s important for us to express some empathy – to agree with them, yes, masks are hot and inconvenient – and help understand their questions, which you may be able to answer to their satisfaction. There are patients that have legitimate questions and a physician caring about how they feel, can make all the difference.”
Physicians can also get involved with the AMA’s #MaskUp campaign, an effort to normalize mask wearing and debunk myths associated with masks. The campaign includes social media materials, slogans doctors can tweet, and profile pictures they can use on social media. The campaign’s toolkit includes images, videos, and information that physicians can share with patients and the public.
Enforcing strong mask policies at your practice and ensuring all staff are modeling appropriate mask behavior is also important, adds Fincher of the ACP. The college recently issued a policy supporting mask usage in community settings.
If a patient conveys an antimask belief, Fincher suggests not directly challenging the person’s views, but listening to them and offering objective data, discussing the science behind masks, and directing them to credible sources.
“Doctors are used to this. We recommend a lot of things to patients that they don’t want to do,” Fincher said. “If a patient feels attacked, they act defensively. But if you base your explanation in more objective terms with data, numbers, and personalize the risks and benefits of a vaccine, a healthy change in behavior, or a medication, then patients are more likely to hear your concerns and do the right thing. Having a long-term relationship with a trusted physician makes all of these issues much easier to discuss and to implement the best plan for the individual patient.”
This article first appeared on Medscape.com.
Abstracts Presented at the 2020 AVAHO Annual Meeting (Digital Edition)
A practical approach to knee OA
CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.
On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.
How would you manage this patient’s care?
The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.1 More than 19% of American adults ages ≥ 45 years have knee OA,1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.3 Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.1 Risk factors for knee OA are outlined in TABLE.1,4-8
Diagnosis: Radiographs are helpful, not essential
The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.1,9,10
Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)
Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.11 Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.
Continue to: Management
Management: Decrease pain, improve function, slow progression
Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. FIGURE 2 contains a summary of the stepwise management of knee OA.
Weight management can slow progression of the disease
Obesity is a causative factor in knee OA.12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.15
Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.16 Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.16 This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.
What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.17
Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.18-22 Weight-bearing strength training, non–weight-bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.23
Continue to: Strengthening of the upper leg muscles...
Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.24 Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.25 In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.26-28
Knee orthoses: Many forms and mixed findings
Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.29
The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.30 Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.31 Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.32 However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.33
Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.34 A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.35
In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.
Continue to: Pharmacotherapy
Pharmacotherapy: Oral agents
Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.
Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.
One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.37 Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.39 However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.39
A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.40
With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.41
Continue to: Glucosamine and chondroitin
Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.
One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.42 However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.42
Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.10,41
In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.
Injections
Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.
Continue to: HA is found naturally...
HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.9 Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.10,41
IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.49 However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.50
AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.
Topicals
Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.
One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.51 One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.52 In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.56
Continue to: Topical capsaicin has shown...
Topical capsaicin has shown some efficacy in treating pain associated with knee OA.57 One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.58 The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.
Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide
IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.59 Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.
Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.64-66
Surgical intervention: A last resort
Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.
There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.67
Continue to: Unicompartmental or "partial"...
Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.
CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.
The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.
She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.
CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].
1. Wallace IJ, Worthington S,Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci. 2017;114:9332-9336.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
3. Vina ER, Kwoh CK. Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol. 2018;30:160-167.
4. Warner SC, Valdes AM. Genetic association studies in osteoarthritis: is it fairytale? Curr Opin Rheumatol. 2017;29:103-109.
5. Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage. 2005;13:769-781.
6. Palazzo C, Nguyen C, Lefevre-Colau MM, et al. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59:134-138.
7. Tanamas S, Hanna FS, Cicuttini FM, et al. Does knee malalignment increase the risk of development and progression of knee osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.
8. Yucesoy B, Charles LE, Baker B, et al. Occupational and genetic risk factors for osteoarthritis: a review. Work. 2015;50:261-273.
9. Trojian TH, Concoff AL, Joy SM, et al. AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med. 2016;50:84-92.
10. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2012;64:465-474.
11. Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord. 2008;9:116.
12. Felson DT, Anderson JJ, Naimark A, et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med. 1988;109:18-24.
13. Yusuf E, Bijsterbosch J, Slagboom PE, et al. Body mass index and alignment and their interaction as risk factors for progression of knees with radiographic signs of osteoarthritis. Osteoarthritis Cartilage. 2011;19:1117-1122.
14. Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic knee osteoarthritis? Arthritis Rheum. 2009;61:329-335.
15. Messier SP, Gutekunst DJ, Davis C, et al. Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum. 2005;52:2026-2032.
16. Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. JAMA. 2013;310:1263-1273.
17. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee: a Cochrane systematic review. Br J Sports Med.
18. Kan L, Zhang J, Yang Y, et al. The effects of yoga on pain, mobility, and quality of life in patients with knee osteoarthritis: a systematic review. Evid Based Complement Alternat Med. 2016;2016:6016532.
19. Chang WD, Chen S, Lee CL, et al. The effects of tai chi chuan on improving mind-body health for knee osteoarthritis patients: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2016;2016:1813979.
20. Takacs J, Krowchuk NM, Garland SJ, et al. Dynamic balance training improves physical function in individuals with knee osteoarthritis: a pilot randomized controlled trial. Arch Phys Med Rehabil. 2017;98:1586-1593.
21. Bartels EM, Juhl CB, Christensen R, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev. 2016;(3):CD005523.
22. Hinman RS, Heywood SE, Day AR. Aquatic physical therapy for hip and knee osteoarthritis: results of a single-blind randomized controlled trial. Phys Ther. 2007;87:32-43.
23. Tanaka R, Ozawa J, Kito N, et al. Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2013;27:1059-1071.
24. Knoop J, Steultjens MP, Roorda LD, et al. Improvement in upper leg muscle strength underlies beneficial effects of exercise therapy in knee osteoarthritis: secondary analysis from a randomised controlled trial. Physiotherapy. 2015;101:171-177.
25. Mat S, Tan MP, Kamaruzzaman SB, et al. Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review. Age Ageing. 2015;44:16-24.
26. Peeler J, Christian M, Cooper J, et al. Managing knee osteoarthritis: the effects of body weight supported physical activity on joint pain, function, and thigh muscle strength. Clin J Sport Med. 2015;25:518-523.
27. Peeler J, Ripat J. The effect of low-load exercise on joint pain, function, and activities of daily living in patients with knee osteoarthritis. Knee. 2018;25:135-145.
28. Takacs J, Anderson JE, Leiter JR, et al. Lower body positive pressure: an emerging technology in the battle against knee osteoarthritis? Clin Interv Aging. 2013;8:983-991.
29. Duivenvoorden T, Brouwer RW, van Raaij TM, et al. Braces and orthoses for treating osteoarthritis of the knee. Cochrane Database Syst Rev. 2015;(3):CD004020.
30. Gohal C, Shanmugaraj A, Tate P, et al. Effectiveness of valgus offloading knee braces in the treatment of medial compartment knee osteoarthritis: a systematic review. Sports Health. 2018;10:500-514.
31. Brouwer RW, van Raaij TM, Verhaar JA, et al. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14:777-783.
32. Lee PY, Winfield TG, Harris SR, et al. Unloading knee brace is a cost-effective method to bridge and delay surgery in unicompartmental knee arthritis. BMJ Open Sport Exerc Med. 2017;2:e000195.
33. Wilson B, Rankin H, Barnes CL. Long-term results of an unloader brace in patients with unicompartmental knee osteoarthritis. Orthopedics. 2011;34:334-347.
34. Cudejko T, van der Esch M, van der Leeden M, et al. Effect of soft braces on pain and physical function in patients with knee osteoarthritis: systematic review with meta-analyses. Arch Phys Med Rehabil. 2018;99:153-163.
35. Cudejko T, van der Esch M, van den Noort JC. Decreased pain and improved dynamic knee instability mediate the beneficial effect of wearing a soft knee brace on activity limitations in persons with knee osteoarthritis. Arthritis Care Res (Hoboken). 2019;71:1036-1043.
36. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
37. da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2017;390:e21-e33.
38. Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46-54.
39. Gregori D, Giacovelli G, Minto C, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320:2564-2579.
40. Puljak L, Marin A, Vrdoljak D, et al. Celecoxib for osteoarthritis. Cochrane Database Syst Rev. 2017;(5):CD009865.
41. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;9:571-576.
42. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
43. Singh JA, Noorbaloochi S, MacDonald R, et al. Chondroitin for osteoarthritis. Cochrane Database Syst Rev. 2015;(1):CD005614.
44. Yang S, Eaton CB, McAlindon TE, et al. Effects of glucosamine and chondroitin on treating knee osteoarthritis: an analysis with marginal structural models. Arthritis Rheumatol. 2015;67:714-723.
45. Ogata T, Yuki Ideno Y, Masami Akai M,et al. Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis. Clin Rheumatol. 2018;37:2479-2487.
46. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2009;(2):CD002946.
47. Bruyèreetal O, Cooper C, Pelletier JP, et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—from evidence-based medicine to the real-life setting. Semin Arthritis Rheum. 2016;45(4 suppl):S3-S11.
48. Ishijima M, Nakamura T, Shimizu K, et al. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res Ther. 2014;16:R18.
49. Juni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. 2015;(10):CD005328.
50. McAlindon TE, LaValley MP, Harvey FW, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317:1967-1975.
51. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;(4):CD007400.
52. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-2012.
53. Wadsworth LT, Kent JD, Holt RJ. Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Curr Med Res Opin. 2016;32:241-250.
54. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-2023.
55. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial. BMC Musculoskelet Disord. 2005;6:44.
56. Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52:642-650.
57. Guedes V, Castro JP, Brito I. Topical capsaicin for pain in osteoarthritis: a literature review. Reumatol Clin. 2018;14:40-45.
58. Persson MSM, Stocks J, Walsh DA, et al. The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials. Osteoarthritis Cartilage. 2018;26:1575-1582.
59. Cole BJ, Karas V, Hussey K, et al. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339-346.
60. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49:657-672.
61. Han Y, Huang H, Pan J, et al. Meta-analysis comparing platelet-rich plasma vs hyaluronic acid injection in patients with knee osteoarthritis. Pain Med. 2019;20:1418-1429.
62. Filardo G, Di Matteo B, Di Martino A, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015;43:1575-1582.
63. Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med. 2019;47:347-354.
64. Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 2015;97:877-888.
65. Conaghan PG, Cohen SB, Berenbaum F, et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70:204-211.
66. Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Jt Surg Am. 2018;100:666–677.
67. Thorlund JB, Juhl CB, Roos EM, et al. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ. 2015;350:h2747.
CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.
On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.
How would you manage this patient’s care?
The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.1 More than 19% of American adults ages ≥ 45 years have knee OA,1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.3 Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.1 Risk factors for knee OA are outlined in TABLE.1,4-8
Diagnosis: Radiographs are helpful, not essential
The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.1,9,10
Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)
Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.11 Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.
Continue to: Management
Management: Decrease pain, improve function, slow progression
Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. FIGURE 2 contains a summary of the stepwise management of knee OA.
Weight management can slow progression of the disease
Obesity is a causative factor in knee OA.12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.15
Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.16 Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.16 This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.
What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.17
Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.18-22 Weight-bearing strength training, non–weight-bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.23
Continue to: Strengthening of the upper leg muscles...
Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.24 Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.25 In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.26-28
Knee orthoses: Many forms and mixed findings
Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.29
The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.30 Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.31 Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.32 However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.33
Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.34 A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.35
In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.
Continue to: Pharmacotherapy
Pharmacotherapy: Oral agents
Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.
Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.
One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.37 Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.39 However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.39
A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.40
With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.41
Continue to: Glucosamine and chondroitin
Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.
One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.42 However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.42
Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.10,41
In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.
Injections
Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.
Continue to: HA is found naturally...
HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.9 Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.10,41
IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.49 However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.50
AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.
Topicals
Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.
One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.51 One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.52 In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.56
Continue to: Topical capsaicin has shown...
Topical capsaicin has shown some efficacy in treating pain associated with knee OA.57 One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.58 The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.
Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide
IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.59 Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.
Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.64-66
Surgical intervention: A last resort
Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.
There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.67
Continue to: Unicompartmental or "partial"...
Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.
CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.
The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.
She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.
CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].
CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.
On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.
How would you manage this patient’s care?
The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.1 More than 19% of American adults ages ≥ 45 years have knee OA,1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.3 Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.1 Risk factors for knee OA are outlined in TABLE.1,4-8
Diagnosis: Radiographs are helpful, not essential
The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.1,9,10
Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)
Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.11 Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.
Continue to: Management
Management: Decrease pain, improve function, slow progression
Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. FIGURE 2 contains a summary of the stepwise management of knee OA.
Weight management can slow progression of the disease
Obesity is a causative factor in knee OA.12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.15
Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.16 Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.16 This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.
What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.17
Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.18-22 Weight-bearing strength training, non–weight-bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.23
Continue to: Strengthening of the upper leg muscles...
Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.24 Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.25 In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.26-28
Knee orthoses: Many forms and mixed findings
Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.29
The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.30 Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.31 Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.32 However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.33
Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.34 A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.35
In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.
Continue to: Pharmacotherapy
Pharmacotherapy: Oral agents
Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.
Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.
One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.37 Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.39 However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.39
A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.40
With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.41
Continue to: Glucosamine and chondroitin
Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.
One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.42 However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.42
Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.10,41
In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.
Injections
Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.
Continue to: HA is found naturally...
HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.9 Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.10,41
IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.49 However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.50
AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.
Topicals
Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.
One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.51 One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.52 In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.56
Continue to: Topical capsaicin has shown...
Topical capsaicin has shown some efficacy in treating pain associated with knee OA.57 One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.58 The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.
Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide
IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.59 Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.
Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.64-66
Surgical intervention: A last resort
Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.
There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.67
Continue to: Unicompartmental or "partial"...
Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.
CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.
The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.
She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.
CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].
1. Wallace IJ, Worthington S,Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci. 2017;114:9332-9336.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
3. Vina ER, Kwoh CK. Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol. 2018;30:160-167.
4. Warner SC, Valdes AM. Genetic association studies in osteoarthritis: is it fairytale? Curr Opin Rheumatol. 2017;29:103-109.
5. Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage. 2005;13:769-781.
6. Palazzo C, Nguyen C, Lefevre-Colau MM, et al. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59:134-138.
7. Tanamas S, Hanna FS, Cicuttini FM, et al. Does knee malalignment increase the risk of development and progression of knee osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.
8. Yucesoy B, Charles LE, Baker B, et al. Occupational and genetic risk factors for osteoarthritis: a review. Work. 2015;50:261-273.
9. Trojian TH, Concoff AL, Joy SM, et al. AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med. 2016;50:84-92.
10. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2012;64:465-474.
11. Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord. 2008;9:116.
12. Felson DT, Anderson JJ, Naimark A, et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med. 1988;109:18-24.
13. Yusuf E, Bijsterbosch J, Slagboom PE, et al. Body mass index and alignment and their interaction as risk factors for progression of knees with radiographic signs of osteoarthritis. Osteoarthritis Cartilage. 2011;19:1117-1122.
14. Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic knee osteoarthritis? Arthritis Rheum. 2009;61:329-335.
15. Messier SP, Gutekunst DJ, Davis C, et al. Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum. 2005;52:2026-2032.
16. Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. JAMA. 2013;310:1263-1273.
17. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee: a Cochrane systematic review. Br J Sports Med.
18. Kan L, Zhang J, Yang Y, et al. The effects of yoga on pain, mobility, and quality of life in patients with knee osteoarthritis: a systematic review. Evid Based Complement Alternat Med. 2016;2016:6016532.
19. Chang WD, Chen S, Lee CL, et al. The effects of tai chi chuan on improving mind-body health for knee osteoarthritis patients: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2016;2016:1813979.
20. Takacs J, Krowchuk NM, Garland SJ, et al. Dynamic balance training improves physical function in individuals with knee osteoarthritis: a pilot randomized controlled trial. Arch Phys Med Rehabil. 2017;98:1586-1593.
21. Bartels EM, Juhl CB, Christensen R, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev. 2016;(3):CD005523.
22. Hinman RS, Heywood SE, Day AR. Aquatic physical therapy for hip and knee osteoarthritis: results of a single-blind randomized controlled trial. Phys Ther. 2007;87:32-43.
23. Tanaka R, Ozawa J, Kito N, et al. Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2013;27:1059-1071.
24. Knoop J, Steultjens MP, Roorda LD, et al. Improvement in upper leg muscle strength underlies beneficial effects of exercise therapy in knee osteoarthritis: secondary analysis from a randomised controlled trial. Physiotherapy. 2015;101:171-177.
25. Mat S, Tan MP, Kamaruzzaman SB, et al. Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review. Age Ageing. 2015;44:16-24.
26. Peeler J, Christian M, Cooper J, et al. Managing knee osteoarthritis: the effects of body weight supported physical activity on joint pain, function, and thigh muscle strength. Clin J Sport Med. 2015;25:518-523.
27. Peeler J, Ripat J. The effect of low-load exercise on joint pain, function, and activities of daily living in patients with knee osteoarthritis. Knee. 2018;25:135-145.
28. Takacs J, Anderson JE, Leiter JR, et al. Lower body positive pressure: an emerging technology in the battle against knee osteoarthritis? Clin Interv Aging. 2013;8:983-991.
29. Duivenvoorden T, Brouwer RW, van Raaij TM, et al. Braces and orthoses for treating osteoarthritis of the knee. Cochrane Database Syst Rev. 2015;(3):CD004020.
30. Gohal C, Shanmugaraj A, Tate P, et al. Effectiveness of valgus offloading knee braces in the treatment of medial compartment knee osteoarthritis: a systematic review. Sports Health. 2018;10:500-514.
31. Brouwer RW, van Raaij TM, Verhaar JA, et al. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14:777-783.
32. Lee PY, Winfield TG, Harris SR, et al. Unloading knee brace is a cost-effective method to bridge and delay surgery in unicompartmental knee arthritis. BMJ Open Sport Exerc Med. 2017;2:e000195.
33. Wilson B, Rankin H, Barnes CL. Long-term results of an unloader brace in patients with unicompartmental knee osteoarthritis. Orthopedics. 2011;34:334-347.
34. Cudejko T, van der Esch M, van der Leeden M, et al. Effect of soft braces on pain and physical function in patients with knee osteoarthritis: systematic review with meta-analyses. Arch Phys Med Rehabil. 2018;99:153-163.
35. Cudejko T, van der Esch M, van den Noort JC. Decreased pain and improved dynamic knee instability mediate the beneficial effect of wearing a soft knee brace on activity limitations in persons with knee osteoarthritis. Arthritis Care Res (Hoboken). 2019;71:1036-1043.
36. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
37. da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2017;390:e21-e33.
38. Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46-54.
39. Gregori D, Giacovelli G, Minto C, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320:2564-2579.
40. Puljak L, Marin A, Vrdoljak D, et al. Celecoxib for osteoarthritis. Cochrane Database Syst Rev. 2017;(5):CD009865.
41. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;9:571-576.
42. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
43. Singh JA, Noorbaloochi S, MacDonald R, et al. Chondroitin for osteoarthritis. Cochrane Database Syst Rev. 2015;(1):CD005614.
44. Yang S, Eaton CB, McAlindon TE, et al. Effects of glucosamine and chondroitin on treating knee osteoarthritis: an analysis with marginal structural models. Arthritis Rheumatol. 2015;67:714-723.
45. Ogata T, Yuki Ideno Y, Masami Akai M,et al. Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis. Clin Rheumatol. 2018;37:2479-2487.
46. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2009;(2):CD002946.
47. Bruyèreetal O, Cooper C, Pelletier JP, et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—from evidence-based medicine to the real-life setting. Semin Arthritis Rheum. 2016;45(4 suppl):S3-S11.
48. Ishijima M, Nakamura T, Shimizu K, et al. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res Ther. 2014;16:R18.
49. Juni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. 2015;(10):CD005328.
50. McAlindon TE, LaValley MP, Harvey FW, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317:1967-1975.
51. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;(4):CD007400.
52. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-2012.
53. Wadsworth LT, Kent JD, Holt RJ. Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Curr Med Res Opin. 2016;32:241-250.
54. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-2023.
55. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial. BMC Musculoskelet Disord. 2005;6:44.
56. Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52:642-650.
57. Guedes V, Castro JP, Brito I. Topical capsaicin for pain in osteoarthritis: a literature review. Reumatol Clin. 2018;14:40-45.
58. Persson MSM, Stocks J, Walsh DA, et al. The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials. Osteoarthritis Cartilage. 2018;26:1575-1582.
59. Cole BJ, Karas V, Hussey K, et al. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339-346.
60. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49:657-672.
61. Han Y, Huang H, Pan J, et al. Meta-analysis comparing platelet-rich plasma vs hyaluronic acid injection in patients with knee osteoarthritis. Pain Med. 2019;20:1418-1429.
62. Filardo G, Di Matteo B, Di Martino A, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015;43:1575-1582.
63. Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med. 2019;47:347-354.
64. Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 2015;97:877-888.
65. Conaghan PG, Cohen SB, Berenbaum F, et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70:204-211.
66. Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Jt Surg Am. 2018;100:666–677.
67. Thorlund JB, Juhl CB, Roos EM, et al. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ. 2015;350:h2747.
1. Wallace IJ, Worthington S,Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci. 2017;114:9332-9336.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
3. Vina ER, Kwoh CK. Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol. 2018;30:160-167.
4. Warner SC, Valdes AM. Genetic association studies in osteoarthritis: is it fairytale? Curr Opin Rheumatol. 2017;29:103-109.
5. Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage. 2005;13:769-781.
6. Palazzo C, Nguyen C, Lefevre-Colau MM, et al. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59:134-138.
7. Tanamas S, Hanna FS, Cicuttini FM, et al. Does knee malalignment increase the risk of development and progression of knee osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.
8. Yucesoy B, Charles LE, Baker B, et al. Occupational and genetic risk factors for osteoarthritis: a review. Work. 2015;50:261-273.
9. Trojian TH, Concoff AL, Joy SM, et al. AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med. 2016;50:84-92.
10. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2012;64:465-474.
11. Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord. 2008;9:116.
12. Felson DT, Anderson JJ, Naimark A, et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med. 1988;109:18-24.
13. Yusuf E, Bijsterbosch J, Slagboom PE, et al. Body mass index and alignment and their interaction as risk factors for progression of knees with radiographic signs of osteoarthritis. Osteoarthritis Cartilage. 2011;19:1117-1122.
14. Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic knee osteoarthritis? Arthritis Rheum. 2009;61:329-335.
15. Messier SP, Gutekunst DJ, Davis C, et al. Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum. 2005;52:2026-2032.
16. Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. JAMA. 2013;310:1263-1273.
17. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee: a Cochrane systematic review. Br J Sports Med.
18. Kan L, Zhang J, Yang Y, et al. The effects of yoga on pain, mobility, and quality of life in patients with knee osteoarthritis: a systematic review. Evid Based Complement Alternat Med. 2016;2016:6016532.
19. Chang WD, Chen S, Lee CL, et al. The effects of tai chi chuan on improving mind-body health for knee osteoarthritis patients: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2016;2016:1813979.
20. Takacs J, Krowchuk NM, Garland SJ, et al. Dynamic balance training improves physical function in individuals with knee osteoarthritis: a pilot randomized controlled trial. Arch Phys Med Rehabil. 2017;98:1586-1593.
21. Bartels EM, Juhl CB, Christensen R, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev. 2016;(3):CD005523.
22. Hinman RS, Heywood SE, Day AR. Aquatic physical therapy for hip and knee osteoarthritis: results of a single-blind randomized controlled trial. Phys Ther. 2007;87:32-43.
23. Tanaka R, Ozawa J, Kito N, et al. Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2013;27:1059-1071.
24. Knoop J, Steultjens MP, Roorda LD, et al. Improvement in upper leg muscle strength underlies beneficial effects of exercise therapy in knee osteoarthritis: secondary analysis from a randomised controlled trial. Physiotherapy. 2015;101:171-177.
25. Mat S, Tan MP, Kamaruzzaman SB, et al. Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review. Age Ageing. 2015;44:16-24.
26. Peeler J, Christian M, Cooper J, et al. Managing knee osteoarthritis: the effects of body weight supported physical activity on joint pain, function, and thigh muscle strength. Clin J Sport Med. 2015;25:518-523.
27. Peeler J, Ripat J. The effect of low-load exercise on joint pain, function, and activities of daily living in patients with knee osteoarthritis. Knee. 2018;25:135-145.
28. Takacs J, Anderson JE, Leiter JR, et al. Lower body positive pressure: an emerging technology in the battle against knee osteoarthritis? Clin Interv Aging. 2013;8:983-991.
29. Duivenvoorden T, Brouwer RW, van Raaij TM, et al. Braces and orthoses for treating osteoarthritis of the knee. Cochrane Database Syst Rev. 2015;(3):CD004020.
30. Gohal C, Shanmugaraj A, Tate P, et al. Effectiveness of valgus offloading knee braces in the treatment of medial compartment knee osteoarthritis: a systematic review. Sports Health. 2018;10:500-514.
31. Brouwer RW, van Raaij TM, Verhaar JA, et al. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14:777-783.
32. Lee PY, Winfield TG, Harris SR, et al. Unloading knee brace is a cost-effective method to bridge and delay surgery in unicompartmental knee arthritis. BMJ Open Sport Exerc Med. 2017;2:e000195.
33. Wilson B, Rankin H, Barnes CL. Long-term results of an unloader brace in patients with unicompartmental knee osteoarthritis. Orthopedics. 2011;34:334-347.
34. Cudejko T, van der Esch M, van der Leeden M, et al. Effect of soft braces on pain and physical function in patients with knee osteoarthritis: systematic review with meta-analyses. Arch Phys Med Rehabil. 2018;99:153-163.
35. Cudejko T, van der Esch M, van den Noort JC. Decreased pain and improved dynamic knee instability mediate the beneficial effect of wearing a soft knee brace on activity limitations in persons with knee osteoarthritis. Arthritis Care Res (Hoboken). 2019;71:1036-1043.
36. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
37. da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2017;390:e21-e33.
38. Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46-54.
39. Gregori D, Giacovelli G, Minto C, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320:2564-2579.
40. Puljak L, Marin A, Vrdoljak D, et al. Celecoxib for osteoarthritis. Cochrane Database Syst Rev. 2017;(5):CD009865.
41. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;9:571-576.
42. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
43. Singh JA, Noorbaloochi S, MacDonald R, et al. Chondroitin for osteoarthritis. Cochrane Database Syst Rev. 2015;(1):CD005614.
44. Yang S, Eaton CB, McAlindon TE, et al. Effects of glucosamine and chondroitin on treating knee osteoarthritis: an analysis with marginal structural models. Arthritis Rheumatol. 2015;67:714-723.
45. Ogata T, Yuki Ideno Y, Masami Akai M,et al. Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis. Clin Rheumatol. 2018;37:2479-2487.
46. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2009;(2):CD002946.
47. Bruyèreetal O, Cooper C, Pelletier JP, et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—from evidence-based medicine to the real-life setting. Semin Arthritis Rheum. 2016;45(4 suppl):S3-S11.
48. Ishijima M, Nakamura T, Shimizu K, et al. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res Ther. 2014;16:R18.
49. Juni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. 2015;(10):CD005328.
50. McAlindon TE, LaValley MP, Harvey FW, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317:1967-1975.
51. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;(4):CD007400.
52. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002-2012.
53. Wadsworth LT, Kent JD, Holt RJ. Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Curr Med Res Opin. 2016;32:241-250.
54. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-2023.
55. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial. BMC Musculoskelet Disord. 2005;6:44.
56. Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52:642-650.
57. Guedes V, Castro JP, Brito I. Topical capsaicin for pain in osteoarthritis: a literature review. Reumatol Clin. 2018;14:40-45.
58. Persson MSM, Stocks J, Walsh DA, et al. The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials. Osteoarthritis Cartilage. 2018;26:1575-1582.
59. Cole BJ, Karas V, Hussey K, et al. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339-346.
60. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49:657-672.
61. Han Y, Huang H, Pan J, et al. Meta-analysis comparing platelet-rich plasma vs hyaluronic acid injection in patients with knee osteoarthritis. Pain Med. 2019;20:1418-1429.
62. Filardo G, Di Matteo B, Di Martino A, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015;43:1575-1582.
63. Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med. 2019;47:347-354.
64. Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 2015;97:877-888.
65. Conaghan PG, Cohen SB, Berenbaum F, et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 2018;70:204-211.
66. Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Jt Surg Am. 2018;100:666–677.
67. Thorlund JB, Juhl CB, Roos EM, et al. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ. 2015;350:h2747.
PRACTICE RECOMMENDATIONS
› Treat pain from knee osteoarthritis (OA) with weight management and low-impact exercise to decrease the risk of disease progression. A
› Prescribe oral or topical nonsteroidal anti-inflammatory drugs to relieve pain from knee OA, as both forms are equally effective. B
› Recommend a medial unloading (valgus) knee brace for short-term relief of medial knee OA. B
› Consider a trial of intra-articular corticosteroids or intra-articular hyaluronic acid derivatives for short-term relief of knee OA pain. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Mounting data support COVID-19 acute pancreatitis
Mounting data support acute pancreatitis as one possible GI manifestation of COVID-19, according to investigators.
While previous case reports suggested that infection with SARS-CoV2 may lead to pancreatitis, this retrospective analysis, which is the largest to date, is the first to offer substantial evidence for this claim, reported lead author Sumant Inamdar, MBBS, of the University of Arkansas, Little Rock, and colleagues.
“It has become increasingly clear that COVID-19 has systemic effects that also includes the gastrointestinal and pancreaticobiliary systems,” the investigators wrote in Gastroenterology. “As islet cells of the pancreas contain ACE2 receptor proteins, SARS-CoV2 can bind to these receptors and cause pancreatic injury.”
For the present analysis, Dr. Inamdar and colleagues reviewed charts from 48,012 patients who were hospitalized in New York between March and June of this year. While pancreatitis is usually diagnosed based on two out of three criteria, disease classification in the study required all three: characteristic upper abdominal pain upon admission, lipase greater than three times the upper limit of normal, and evidence of pancreatitis on cross-sectional imaging.
“[B]y including all three criteria for pancreatitis in our definition, we may be underestimating the rate of pancreatitis,” the investigators wrote. “However, we felt including diagnostic lipase levels and imaging was important for the accuracy of the diagnosis.”
Primary outcomes included mechanical ventilation, length of stay, development of pancreatic necrosis, and mortality. Outcomes were compared between patients with and without COVID-19.
Out of 48,012 hospitalized patients, 11,883 (24.75%) tested positive for SARS-CoV2. Across the entire population, 189 patients had pancreatitis (0.39%), and of these, 32 (17%) also had COVID-19. This translates to a point prevalence for pancreatitis of 0.27% for patients hospitalized with COVID-19.
Among patients with pancreatitis who did not have COVID-19, the most common etiologies for pancreatitis were gallstones (34%) and alcohol (37%), compared with just 16% and 6% of SARS-CoV2-positive cases of pancreatitis, respectively. Idiopathic pancreatitis was significantly more common among patients with COVID-19 than those without (69% vs 21%; P less than .0001).
Black or Hispanic patients with pancreatitis were 4-5 times more likely to have COVID-19 than patients with pancreatitis who were white. Across all races/ethnicities, patients with pancreatitis and COVID-19 more often required mechanical ventilation (odds ratio [OR], 5.65) and longer hospital stays (OR, 3.22), compared with those who had pancreatitis alone. While rates of mortality and pancreatic necrosis showed similar trends, associations with COVID-19 were not statistically significant.
“These findings support the notion that pancreatitis should be included in the list of GI manifestations of COVID-19,” the investigators wrote.
When caring for patients with COVID-19, Dr. Inamdar and colleagues recommended that clinicians pay close attention to any history of abdominal pain, and consider testing serum lipase levels.
“Further large studies are needed to confirm our findings,” they concluded.
Avinash Ketwaroo, MD, of Baylor College of Medicine in Houston, agreed that more work is needed; in the meantime, he suggested that evidence is now strong enough for clinicians to take notice.
“Overall, this study adds further weight to COVID-19 acute pancreatitis,” he said. “Larger studies, and convincing pathophysiologic data, will be needed to confirm COVID-19 as a cause of acute pancreatitis. However, there appears to be enough circumstantial evidence to consider a COVID-19 diagnosis in patients presenting with acute pancreatitis.”
He noted that the new clinical evidence also stands on a solid theoretical foundation.
“Viruses, especially mumps and coxsackie, have long been known to cause acute pancreatitis,” he said. “Additionally, the ACE2 receptor is present on pancreatic beta-cells and may mediate COVID-19 induced pancreatitis.”
Along with larger observational studies, Dr. Ketwaroo suggested that a number of interventional questions remain unanswered.
“While most acute pancreatitis is treated with supportive care, could proven therapies for COVID-19, such as steroids, also mitigate COVID-19 acute pancreatitis?” he asked. “Is COVID-19 a cofactor for acute pancreatitis caused by alcohol or endoscopic retrograde cholangiopancreatography? We await further information from an active area of research.”
The investigators disclosed relationships with Boston Scientific, Olympus, Fujifilm, and others.
SOURCE: Inamdar S et al. Gastroenterology. 2020 Aug 26. doi: 10.1053/j.gastro.2020.08.044.
Share AGA GI Patient Center content to help your patients understand the symptoms and complications of pancreatitis at http://ow.ly/j1AN30r8ZDa.
This story was updated on 9/14/2020.
Mounting data support acute pancreatitis as one possible GI manifestation of COVID-19, according to investigators.
While previous case reports suggested that infection with SARS-CoV2 may lead to pancreatitis, this retrospective analysis, which is the largest to date, is the first to offer substantial evidence for this claim, reported lead author Sumant Inamdar, MBBS, of the University of Arkansas, Little Rock, and colleagues.
“It has become increasingly clear that COVID-19 has systemic effects that also includes the gastrointestinal and pancreaticobiliary systems,” the investigators wrote in Gastroenterology. “As islet cells of the pancreas contain ACE2 receptor proteins, SARS-CoV2 can bind to these receptors and cause pancreatic injury.”
For the present analysis, Dr. Inamdar and colleagues reviewed charts from 48,012 patients who were hospitalized in New York between March and June of this year. While pancreatitis is usually diagnosed based on two out of three criteria, disease classification in the study required all three: characteristic upper abdominal pain upon admission, lipase greater than three times the upper limit of normal, and evidence of pancreatitis on cross-sectional imaging.
“[B]y including all three criteria for pancreatitis in our definition, we may be underestimating the rate of pancreatitis,” the investigators wrote. “However, we felt including diagnostic lipase levels and imaging was important for the accuracy of the diagnosis.”
Primary outcomes included mechanical ventilation, length of stay, development of pancreatic necrosis, and mortality. Outcomes were compared between patients with and without COVID-19.
Out of 48,012 hospitalized patients, 11,883 (24.75%) tested positive for SARS-CoV2. Across the entire population, 189 patients had pancreatitis (0.39%), and of these, 32 (17%) also had COVID-19. This translates to a point prevalence for pancreatitis of 0.27% for patients hospitalized with COVID-19.
Among patients with pancreatitis who did not have COVID-19, the most common etiologies for pancreatitis were gallstones (34%) and alcohol (37%), compared with just 16% and 6% of SARS-CoV2-positive cases of pancreatitis, respectively. Idiopathic pancreatitis was significantly more common among patients with COVID-19 than those without (69% vs 21%; P less than .0001).
Black or Hispanic patients with pancreatitis were 4-5 times more likely to have COVID-19 than patients with pancreatitis who were white. Across all races/ethnicities, patients with pancreatitis and COVID-19 more often required mechanical ventilation (odds ratio [OR], 5.65) and longer hospital stays (OR, 3.22), compared with those who had pancreatitis alone. While rates of mortality and pancreatic necrosis showed similar trends, associations with COVID-19 were not statistically significant.
“These findings support the notion that pancreatitis should be included in the list of GI manifestations of COVID-19,” the investigators wrote.
When caring for patients with COVID-19, Dr. Inamdar and colleagues recommended that clinicians pay close attention to any history of abdominal pain, and consider testing serum lipase levels.
“Further large studies are needed to confirm our findings,” they concluded.
Avinash Ketwaroo, MD, of Baylor College of Medicine in Houston, agreed that more work is needed; in the meantime, he suggested that evidence is now strong enough for clinicians to take notice.
“Overall, this study adds further weight to COVID-19 acute pancreatitis,” he said. “Larger studies, and convincing pathophysiologic data, will be needed to confirm COVID-19 as a cause of acute pancreatitis. However, there appears to be enough circumstantial evidence to consider a COVID-19 diagnosis in patients presenting with acute pancreatitis.”
He noted that the new clinical evidence also stands on a solid theoretical foundation.
“Viruses, especially mumps and coxsackie, have long been known to cause acute pancreatitis,” he said. “Additionally, the ACE2 receptor is present on pancreatic beta-cells and may mediate COVID-19 induced pancreatitis.”
Along with larger observational studies, Dr. Ketwaroo suggested that a number of interventional questions remain unanswered.
“While most acute pancreatitis is treated with supportive care, could proven therapies for COVID-19, such as steroids, also mitigate COVID-19 acute pancreatitis?” he asked. “Is COVID-19 a cofactor for acute pancreatitis caused by alcohol or endoscopic retrograde cholangiopancreatography? We await further information from an active area of research.”
The investigators disclosed relationships with Boston Scientific, Olympus, Fujifilm, and others.
SOURCE: Inamdar S et al. Gastroenterology. 2020 Aug 26. doi: 10.1053/j.gastro.2020.08.044.
Share AGA GI Patient Center content to help your patients understand the symptoms and complications of pancreatitis at http://ow.ly/j1AN30r8ZDa.
This story was updated on 9/14/2020.
Mounting data support acute pancreatitis as one possible GI manifestation of COVID-19, according to investigators.
While previous case reports suggested that infection with SARS-CoV2 may lead to pancreatitis, this retrospective analysis, which is the largest to date, is the first to offer substantial evidence for this claim, reported lead author Sumant Inamdar, MBBS, of the University of Arkansas, Little Rock, and colleagues.
“It has become increasingly clear that COVID-19 has systemic effects that also includes the gastrointestinal and pancreaticobiliary systems,” the investigators wrote in Gastroenterology. “As islet cells of the pancreas contain ACE2 receptor proteins, SARS-CoV2 can bind to these receptors and cause pancreatic injury.”
For the present analysis, Dr. Inamdar and colleagues reviewed charts from 48,012 patients who were hospitalized in New York between March and June of this year. While pancreatitis is usually diagnosed based on two out of three criteria, disease classification in the study required all three: characteristic upper abdominal pain upon admission, lipase greater than three times the upper limit of normal, and evidence of pancreatitis on cross-sectional imaging.
“[B]y including all three criteria for pancreatitis in our definition, we may be underestimating the rate of pancreatitis,” the investigators wrote. “However, we felt including diagnostic lipase levels and imaging was important for the accuracy of the diagnosis.”
Primary outcomes included mechanical ventilation, length of stay, development of pancreatic necrosis, and mortality. Outcomes were compared between patients with and without COVID-19.
Out of 48,012 hospitalized patients, 11,883 (24.75%) tested positive for SARS-CoV2. Across the entire population, 189 patients had pancreatitis (0.39%), and of these, 32 (17%) also had COVID-19. This translates to a point prevalence for pancreatitis of 0.27% for patients hospitalized with COVID-19.
Among patients with pancreatitis who did not have COVID-19, the most common etiologies for pancreatitis were gallstones (34%) and alcohol (37%), compared with just 16% and 6% of SARS-CoV2-positive cases of pancreatitis, respectively. Idiopathic pancreatitis was significantly more common among patients with COVID-19 than those without (69% vs 21%; P less than .0001).
Black or Hispanic patients with pancreatitis were 4-5 times more likely to have COVID-19 than patients with pancreatitis who were white. Across all races/ethnicities, patients with pancreatitis and COVID-19 more often required mechanical ventilation (odds ratio [OR], 5.65) and longer hospital stays (OR, 3.22), compared with those who had pancreatitis alone. While rates of mortality and pancreatic necrosis showed similar trends, associations with COVID-19 were not statistically significant.
“These findings support the notion that pancreatitis should be included in the list of GI manifestations of COVID-19,” the investigators wrote.
When caring for patients with COVID-19, Dr. Inamdar and colleagues recommended that clinicians pay close attention to any history of abdominal pain, and consider testing serum lipase levels.
“Further large studies are needed to confirm our findings,” they concluded.
Avinash Ketwaroo, MD, of Baylor College of Medicine in Houston, agreed that more work is needed; in the meantime, he suggested that evidence is now strong enough for clinicians to take notice.
“Overall, this study adds further weight to COVID-19 acute pancreatitis,” he said. “Larger studies, and convincing pathophysiologic data, will be needed to confirm COVID-19 as a cause of acute pancreatitis. However, there appears to be enough circumstantial evidence to consider a COVID-19 diagnosis in patients presenting with acute pancreatitis.”
He noted that the new clinical evidence also stands on a solid theoretical foundation.
“Viruses, especially mumps and coxsackie, have long been known to cause acute pancreatitis,” he said. “Additionally, the ACE2 receptor is present on pancreatic beta-cells and may mediate COVID-19 induced pancreatitis.”
Along with larger observational studies, Dr. Ketwaroo suggested that a number of interventional questions remain unanswered.
“While most acute pancreatitis is treated with supportive care, could proven therapies for COVID-19, such as steroids, also mitigate COVID-19 acute pancreatitis?” he asked. “Is COVID-19 a cofactor for acute pancreatitis caused by alcohol or endoscopic retrograde cholangiopancreatography? We await further information from an active area of research.”
The investigators disclosed relationships with Boston Scientific, Olympus, Fujifilm, and others.
SOURCE: Inamdar S et al. Gastroenterology. 2020 Aug 26. doi: 10.1053/j.gastro.2020.08.044.
Share AGA GI Patient Center content to help your patients understand the symptoms and complications of pancreatitis at http://ow.ly/j1AN30r8ZDa.
This story was updated on 9/14/2020.
FROM GASTROENTEROLOGY
Insomnia + COPD linked to more outpatient, ED visits
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
FROM SLEEP 2020
Should beta-blockers be used in portal hypertension?
Dear colleagues and friends,
Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].
Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
Beta-blockers in portal hypertension – Yes!
BY GUADALUPE GARCIA-TSAO, MD
Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.
Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).
Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.
A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.1 More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).
In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.2 More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.3 This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.
In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.2 In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.4
There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.1,4
Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.5 In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.6 This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.
In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
References
1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.
2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.
3. Villanueva C et al. Lancet. 2019;393:1597-608.
4. Albillos A et al. Hepatology. 2017;66:1219-31.
5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.
6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.
Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.
Can be a double-edged blade too dangerous to wield
BY MARWAN S. GHABRIL, MD, AGAF
Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.
The pathophysiology of portal hypertension 
Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.
The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
Reported clinical experiences
The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.2
In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.3 There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.
It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.4,5
When is caution due?
Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.
In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
References
1. Serste T et al. Hepatology. 2010;52:1017-22.
2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.
3. Bossen L et al. Hepatology. 2016;63:1968-76.
4. Giannelli V et al. J Hepatol. 2020;72:463-71.
5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.
Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.
Dear colleagues and friends,
Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].
Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
Beta-blockers in portal hypertension – Yes!
BY GUADALUPE GARCIA-TSAO, MD
Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.
Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).
Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.
A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.1 More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).
In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.2 More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.3 This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.
In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.2 In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.4
There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.1,4
Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.5 In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.6 This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.
In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
References
1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.
2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.
3. Villanueva C et al. Lancet. 2019;393:1597-608.
4. Albillos A et al. Hepatology. 2017;66:1219-31.
5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.
6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.
Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.
Can be a double-edged blade too dangerous to wield
BY MARWAN S. GHABRIL, MD, AGAF
Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.
The pathophysiology of portal hypertension
Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.
The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
Reported clinical experiences
The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.2
In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.3 There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.
It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.4,5
When is caution due?
Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.
In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
References
1. Serste T et al. Hepatology. 2010;52:1017-22.
2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.
3. Bossen L et al. Hepatology. 2016;63:1968-76.
4. Giannelli V et al. J Hepatol. 2020;72:463-71.
5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.
Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.
Dear colleagues and friends,
Thank you for your continued support of the Perspectives debates. In this edition, Dr. Guadalupe Garcia-Tsao and Dr. Marwan Ghabril discuss the rationale for and against beta-blocker therapy in portal hypertension, and ultimately highlight the nuances required for appropriate decision-making. This topic invariably generates controversy and debate, and is broadly relevant to general GI and hepatology practices. I hope you will find it as informative as I did, and I welcome your comments and suggestions for future topics at [email protected].
Charles J. Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
Beta-blockers in portal hypertension – Yes!
BY GUADALUPE GARCIA-TSAO, MD
Portal hypertension is the main consequence of cirrhosis and is responsible for most of its complications. In compensated cirrhosis, a threshold portal pressure gradient, as determined by the hepatic venous pressure gradient (HVPG), of at least 10 mm Hg is the strongest predictor of clinical decompensation (ascites, variceal hemorrhage, or encephalopathy) which is, in turn, the main determinant of death in cirrhosis.
Portal hypertension is initially caused by an increase in intrahepatic resistance that leads to mild portal hypertension (HVPG, 5-10 mm Hg) but is then enhanced and maintained by an increase in portal venous inflow that leads to clinically significant portal hypertension (HVPG, at least 10 mm Hg).
Portal pressure can be reduced by either ameliorating intrahepatic resistance (which is mostly caused by structural changes that are difficult to reverse) and/or by decreasing portal vein blood inflow (the most modifiable pathogenic mechanism). For over 30 years, treatment of portal hypertension has been based on the use of nonselective beta-blockers (NSBB), drugs that decrease portal pressure through a reduction in splanchnic blood flow. Reduction in portal pressure is greater with NSBB (propranolol, nadolol) than with selective beta-blockers because, as demonstrated experimentally, the main portal pressure–reducing effect stems from splanchnic vasoconstriction because of beta2-adrenergic blockade. This has been confirmed in patients with cirrhosis, in whom the reduction in HVPG is greater with NSBB than with selective BB. On the other hand, carvedilol, an NSBB that also has a vasodilatory alpha1 adrenergic blocking effect, has a greater effect in reducing HVPG, compared with traditional NSBB.
A significant decrease in portal pressure has been associated with better outcomes in cirrhosis. A favorable portal pressure reduction (“response”) has been traditionally defined as a decrease in HVPG below 12 mm Hg or greater than 20% from baseline, although even decreases of 10% are associated with better outcomes. Initial studies had been focused on variceal hemorrhage, a complication that is clearly related to portal hypertension. In this setting, reducing portal pressure clearly leads to a decreased in the incidence of variceal hemorrhage and a decrease in mortality.1 More recently, the focus has been on preventing decompensation (in compensated cirrhosis) and preventing further decompensation/death (in decompensated cirrhosis).
In compensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices (therefore with clinically significant portal hypertension) without ascites who were NSBB hemodynamic responders, had a reduced risk of developing not only variceal hemorrhage but also ascites and/or encephalopathy, and had lower mortality.2 More importantly, a recent seminal randomized, double-blind, placebo-controlled trial performed in patients with compensated cirrhosis and clinically significant portal hypertension with no or small varices, showed that NSBB (propranolol or carvedilol) led to a significantly lower incidence of decompensation, with ascites being the single event that was significantly lower in the NSBB group.3 This study thereby demonstrates that NSBBs not only reduce the risk of variceal hemorrhage, as previously demonstrated, but also significantly reduces the probability of developing ascites, the most common complication of cirrhosis.
In decompensated cirrhosis, a recent meta-analysis of clinical trials of prevention of variceal hemorrhage showed that patients with varices and ascites (decompensated) who were NSBB responders, had a reduced risk of developing not only variceal hemorrhage but also refractory ascites, spontaneous bacterial peritonitis and/or hepatorenal syndrome, and also had a lower mortality.2 In patients with variceal hemorrhage, the recommended therapy to prevent recurrent variceal hemorrhage is the combination of NSBB plus variceal ligation but this is based on trials that combined compensated and decompensated patients. An individual patient data meta-analysis of these trials showed that, in the group of patients with decompensated Child-Pugh class B/C cirrhosis, rebleeding and mortality were higher with ligation alone, compared with combined therapy with NSBBs and ligation, underlining that NSBB is the key element of combination therapy in these patients.4
There is a fading controversy regarding the potential for increased mortality with the use of NSBBs in patients with refractory ascites and SBP, reported in two retrospective studies.5 These studies lacked information regarding the number of patients in whom NSBBs were withdrawn before the last observation and number of patients in whom NSBBs were started in the course of follow-up. Notably, a recent meta-analysis that included these and subsequent retrospective studies, encompassing a collective of over 1,300 patients, demonstrated that NSBB use in patients with ascites is not related to increased mortality.1,4
Nevertheless, NSBBs should be used cautiously in patients with cirrhosis and ascites. Hemodynamic alterations typical of decompensated cirrhosis are maximal in patients with refractory ascites and spontaneous bacterial peritonitis and the use of NSBB in this setting could lead to worsening hemodynamics, with decreased mean arterial pressure and renal perfusion that could in turn lead to acute kidney injury and death. In studies showing a deleterious effect of NSBB, the mean arterial pressure was significantly lower in patients in the NSBB group.5 In a recent retrospective study, the beneficial effect of NSBBs in patients with refractory ascites, spontaneous bacterial peritonitis, and acute-on-chronic liver failure appeared to apply only to those with a mean arterial pressure of at least 65 mm Hg.6 This evidence has led to guideline recommendations that limit the dose of NSBB to a maximum of 160 mg/day for propranolol or 80 mg/day for nadolol in patients with ascites with close follow-up of arterial blood pressure. Carvedilol should preferably not be used. In the presence of a systolic blood pressure <90 mm Hg or acute kidney injury, NSBBs should be dose-reduced or discontinued. If a precipitant for hypotension is identified (e.g., spontaneous bacterial peritonitis), NSBB can be reinitiated once the precipitating event is resolved and hypotension/acute kidney injury has resolved.
In conclusion, NSBBs are a definite “yes” in the management of cirrhosis and portal hypertension as they prevent poor outcomes (including death) in patients with both compensated and decompensated cirrhosis. In patients with ascites and spontaneous bacterial peritonitis, NSBBs could have deleterious effects but these can be prevented by careful monitoring of blood pressure.
References
1. D’Amico G et al. Gastroenterology. 2006;131:1611-24.
2. Turco L et al. Clin Gastroenterol Hepatol. 2020;18:313-27.
3. Villanueva C et al. Lancet. 2019;393:1597-608.
4. Albillos A et al. Hepatology. 2017;66:1219-31.
5. Garcia-Tsao G. J Hepatol. 2016 Mar;64(3):532-4.
6. Tergast TL et al. Aliment Pharmacol. Ther 2019;50:696-706.
Dr. Garcia-Tsao is professor of medicine, digestive diseases; chief, digestive diseases, Veterans Affairs Connecticut Healthcare System; director, clinical and translational core, Yale Liver Center; program director, VA Connecticut Hepatitis C Resource Center, New Haven. She has no conflicts.
Can be a double-edged blade too dangerous to wield
BY MARWAN S. GHABRIL, MD, AGAF
Nonselective beta-blockers (NSBB) are a cornerstone in the primary and secondary prophylaxis of variceal bleeding in patients with cirrhosis and clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) of at least 10 mm Hg. In the absence of routine HVPG measurement in most clinical practices, NSBB therapy is targeted to a 25% heart rate reduction or target heart rate of 55-60 beats per minute. There is ample evidence supporting this indication for NSBB as summarized in the Baveno VI consensus recommendations in a wide range of liver disease severity, encompassing patients with low-risk small esophageal varices to those with large varices, stigmata, and advanced Child-Pugh class. Tasked with the contrarian perspective on NSBB use, the argument for caution hinges on observations that disease progression can shift the balance of risk and reward to NSBB minimization or avoidance. Understanding the hyperdynamic circulation in worsening portal hypertension of cirrhosis is paramount to these considerations.
The pathophysiology of portal hypertension
Portal hypertension arises as a result of both increased portal venous inflow and increased hepatic sinusoidal resistance and is characterized by splanchnic and systemic vasodilation and reduced effective systemic arterial volume. Compensatory mechanisms include systemic neurohormonal activation, increased heart rate and cardiac output, sodium and water retention (increased plasma volume), and vasoconstrictor system activation. These mechanisms suffice in restoring effective arterial volume initially but also contribute to increased splanchnic/portal inflow and portal hypertension. In advanced decompensation the cardiovascular reserve is overwhelmed with progressive systemic vasodilation, worsening sodium and water retention, vasoconstriction of vital organ vascular beds and an ineffective hyperdynamic state (tachycardia, inadequate cardiac output, and systemic hypotension). This pathophysiological state is heralded clinically by the development of worsening or refractory ascites, and belies the development of other complications of advanced cirrhosis including hyponatremia and hepatorenal syndrome.
The beneficial effects of NSBB in decreasing portal hypertension are mediated by inhibition of splanchnic vasodilation and cardiac effects (reduced heart rate and cardiac output) leading to reduced portal inflow. However, these cardiac effects can be deleterious to systemic hemodynamics in more advanced disease, particularly with acute insults that exacerbate arterial hypovolemia such as bleeding or infection. As such, blunting of sympathetic drive by NSBB carries different degrees of tolerance and risk depending on the hemodynamic reserve in the hyperdynamic state.
Reported clinical experiences
The controversy over NSBB use in advanced cirrhosis arises out of heterogeneous, commonly retrospective datasets and nonrandomized cohorts, with conflicting reports of positive, negative, or neutral effects on mortality and acute kidney injury. Not surprisingly, studies describing detrimental effects of NSBB are based on patients with strictly defined refractory ascites or those with spontaneous bacterial peritonitis.1,2 Importantly, these studies also describe significantly lower blood pressure in at-risk NSBB treated patients, This baseline hemodynamic difference is either not observed,or not explicitly compared in studies/subcohorts with decreased or unaffected mortality with NSBB use in advanced cirrhosis.2
In the largest prospective study of NSBB in cirrhosis with ascites (which used data from three randomized satavaptan trials), NSBB users and nonusers were more closely matched for baseline mean arterial pressure.3 There was no effect of NSBB on mortality but there was a 29% rate of NSBB discontinuation (i.e., intolerance) during the year of follow-up. Predictors of NSBB discontinuation were hospitalization, variceal bleeding, infection, hepatorenal syndrome, Child-Pugh class C, and refractory ascites. Furthermore, NSBB discontinuation was associated with a notable increase in mortality. Similarly, clinically driven discontinuation of NSBB was observed in half of hospitalized patients with acute-on-chronic liver failure in the prospective CANONIC study, and was also associated with significantly higher short-term mortality.
It is possible that NSBB tolerance may select patients with adequate hemodynamic reserve despite the severity of other liver decompensations. Conversely, intolerance of therapeutic NSBB may signify evolving inadequacy of hemodynamic reserve, giving rise to two distinctly different risk/benefit profiles. This double-edged blade perspective is supported by findings of impaired cardiac output in patients with refractory ascites with impaired renal perfusion, and increased wait-list mortality with NSBB use in patients with compromised global cardiac function.4,5
When is caution due?
Rather than a “therapeutic window” that is either wide open or suddenly shut, in nonhospitalized patients risk is on a continuum and there are no agreed upon liver-specific parameters that define strict barriers to NSBB treatment. Refractory ascites may not absolutely define the closure of this window but should put clinicians on notice for a patient’s vulnerability. The Baveno VI recommendations echo the need for caution, with NSBB in refractory ascites with close monitoring of blood pressure, serum sodium, and creatinine. Treatment cessation, reduction or temporary withholding, and careful reintroduction (with reversible insults) are advised in patients with systolic blood pressure <90 mm Hg, serum Na <130 mEq/L, or those with acute kidney injury.
In the absence of randomized trials that account for cirrhotic cardiomyopathy and cardiac reserve, the risks and putative nonvariceal benefits of NSBB (e.g., reducing gut bacterial translocation) are not truly defined in this patient population. We lack HVPG-based or surrogate assessments in routine practice to determine which patients are hemodynamically benefiting from NSBB therapy, or reliable indicators of imminent NSBB intolerance or risk. While the indications for NSBB may expand to prevention of decompensation, serious questions about their safety are being asked in advanced decompensation. Poor tolerance of therapeutic NSBB dosing and unquantified, but likely negative, impact on quality of life raise additional questions. In a shared decision-making partnership, the patient’s perspective on the utility, tolerance, and monitoring of NSBB therapy in preventing variceal bleeding is vital, particularly when there are endoscopic or earlier shunting alternatives. “Primum non nocere” is not a gladiatorial cry, and in the wrong patients NSBB can be a double-edged blade too dangerous to wield.
References
1. Serste T et al. Hepatology. 2010;52:1017-22.
2. Mandorfer M et al. Gastroenterology. 2014;146:1680-90 e1.
3. Bossen L et al. Hepatology. 2016;63:1968-76.
4. Giannelli V et al. J Hepatol. 2020;72:463-71.
5. Tellez L et al. J Hepatol. 2020 May 20. doi: 10.1016/j.jhep.2020.05.011.
Dr. Ghabril is a gastroenterologist with the Indiana University, Indianapolis. He has no conflicts.
Combination approach to melasma treatment yields best results
When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.
“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”
While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”
Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”
While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.
In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.
In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.
When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”
In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm2 with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”
In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm3. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”
Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”
Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”
Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.
In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.
Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”
In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.
The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.
Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.
She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”
Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.
When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.
“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”
While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”
Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”
While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.
In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.
In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.
When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”
In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm2 with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”
In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm3. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”
Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”
Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”
Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.
In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.
Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”
In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.
The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.
Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.
She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”
Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.
When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.
“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”
While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”
Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”
While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.
In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.
In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.
When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”
In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm2 with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”
In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm3. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”
Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”
Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”
Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.
In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.
Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”
In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.
The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.
Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.
She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”
Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.
EXPERT ANALYSIS FROM MOA 2020
A woman with an asymptomatic eruption on her palms after exposure to water
This eruption can be accompanied by a mild burning or tingling sensation, which will subside with the rest of the symptoms in minutes to hours after drying.1
AWP is most frequently associated with cystic fibrosis (CF).2 It can be observed in up to 80% of CF patients and is considered a clinical sign of the disease. AWP can be present in CF carriers to a lesser extent,2,4 and has also been associated with focal hyperhidrosis, atopic dermatitis, Raynaud phenomenon, and COX-2 inhibitor use.5
While a definitive cause is unknown, it is thought that AWP is caused by dysregulation of sweat glands in the palms through increased expression of aquaporin, a protein crucial in the transport of water between cells.3
AWP is quite rare and benign in nature. However, because of its strong association with CF, genetic screening should be considered in asymptomatic patients. Our patient had been screened in the past and is not a CF carrier. Often, the itching or burning associated with CF is mild and easily controlled. The patient was placed on low dose isotretinoin for treatment of her acne. Interestingly, the patient claimed her eruption no longer appeared after starting isotretinoin therapy. To our knowledge, this is the first reported case of AWP resolving with isotretinoin use.
This case and photo were submitted by Mr. Birk, University of Texas, Austin, Texas; and Dr. Mamelak, Sanova Dermatology, in Austin. Donna Bilu Martin, MD, edited the column.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].
References
1. Katz M, Ramot Y. CMAJ. 2015 Dec 8;187(18):E515.
2. Tolland JP et al. Dermatology. 2010;221(4):326-30.
3. Kabashima K et al. J Am Acad Dermatol. 2008 Aug;59(2 Suppl 1):S28-32.
4. Gild R et al. Br J Dermatol. 2010 Nov;163(5):1082-4.
5. Glatz M and Muellegger RR. BMJ Case Rep. 2014. doi: 10.1136/bcr-2014-203929.
This eruption can be accompanied by a mild burning or tingling sensation, which will subside with the rest of the symptoms in minutes to hours after drying.1
AWP is most frequently associated with cystic fibrosis (CF).2 It can be observed in up to 80% of CF patients and is considered a clinical sign of the disease. AWP can be present in CF carriers to a lesser extent,2,4 and has also been associated with focal hyperhidrosis, atopic dermatitis, Raynaud phenomenon, and COX-2 inhibitor use.5
While a definitive cause is unknown, it is thought that AWP is caused by dysregulation of sweat glands in the palms through increased expression of aquaporin, a protein crucial in the transport of water between cells.3
AWP is quite rare and benign in nature. However, because of its strong association with CF, genetic screening should be considered in asymptomatic patients. Our patient had been screened in the past and is not a CF carrier. Often, the itching or burning associated with CF is mild and easily controlled. The patient was placed on low dose isotretinoin for treatment of her acne. Interestingly, the patient claimed her eruption no longer appeared after starting isotretinoin therapy. To our knowledge, this is the first reported case of AWP resolving with isotretinoin use.
This case and photo were submitted by Mr. Birk, University of Texas, Austin, Texas; and Dr. Mamelak, Sanova Dermatology, in Austin. Donna Bilu Martin, MD, edited the column.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].
References
1. Katz M, Ramot Y. CMAJ. 2015 Dec 8;187(18):E515.
2. Tolland JP et al. Dermatology. 2010;221(4):326-30.
3. Kabashima K et al. J Am Acad Dermatol. 2008 Aug;59(2 Suppl 1):S28-32.
4. Gild R et al. Br J Dermatol. 2010 Nov;163(5):1082-4.
5. Glatz M and Muellegger RR. BMJ Case Rep. 2014. doi: 10.1136/bcr-2014-203929.
This eruption can be accompanied by a mild burning or tingling sensation, which will subside with the rest of the symptoms in minutes to hours after drying.1
AWP is most frequently associated with cystic fibrosis (CF).2 It can be observed in up to 80% of CF patients and is considered a clinical sign of the disease. AWP can be present in CF carriers to a lesser extent,2,4 and has also been associated with focal hyperhidrosis, atopic dermatitis, Raynaud phenomenon, and COX-2 inhibitor use.5
While a definitive cause is unknown, it is thought that AWP is caused by dysregulation of sweat glands in the palms through increased expression of aquaporin, a protein crucial in the transport of water between cells.3
AWP is quite rare and benign in nature. However, because of its strong association with CF, genetic screening should be considered in asymptomatic patients. Our patient had been screened in the past and is not a CF carrier. Often, the itching or burning associated with CF is mild and easily controlled. The patient was placed on low dose isotretinoin for treatment of her acne. Interestingly, the patient claimed her eruption no longer appeared after starting isotretinoin therapy. To our knowledge, this is the first reported case of AWP resolving with isotretinoin use.
This case and photo were submitted by Mr. Birk, University of Texas, Austin, Texas; and Dr. Mamelak, Sanova Dermatology, in Austin. Donna Bilu Martin, MD, edited the column.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].
References
1. Katz M, Ramot Y. CMAJ. 2015 Dec 8;187(18):E515.
2. Tolland JP et al. Dermatology. 2010;221(4):326-30.
3. Kabashima K et al. J Am Acad Dermatol. 2008 Aug;59(2 Suppl 1):S28-32.
4. Gild R et al. Br J Dermatol. 2010 Nov;163(5):1082-4.
5. Glatz M and Muellegger RR. BMJ Case Rep. 2014. doi: 10.1136/bcr-2014-203929.
Rash, muscle weakness, and confusion
The constellation of symptoms was suggestive of Lyme disease, although connective tissue disease and syphilis were also considered. Two punch biopsies were performed in the office, and erythrocyte sedimentation rate (ESR), complete blood cell count (CBC), international normalized ratio (INR), comprehensive metabolic panel (CMP), Lyme enzyme-linked immunosorbent assay (ELISA) antibody panel, and rapid plasma reagin (RPR) laboratory tests were ordered.
Immediately available laboratory results included ESR, CBC, INR, and CMP. Findings were notable for elevated INR, as well as elevated alanine aminotransferase and aspartate transaminase. The transaminitis suggested myopathy and was consistent with clinical muscle weakness. RPR testing was negative.
Because of the confusion, severity of muscle weakness, and plausibility of early encephalopathy with Lyme disease, the patient was admitted to the hospital for further work-up. Lumbar puncture was delayed until his INR was reduced, but subsequently was found to be normal. He received intravenous (IV) ceftriaxone (2 g/d) empirically for possible early disseminated disease with neurologic complications. His confusion, muscle weakness, and transaminitis rapidly improved.
His Lyme antibody panel was positive for IgM after his third day of hospitalization. A reflexive confirmatory western blot for IgG was not positive on the initial set of labs but was positive when redrawn 4 weeks after this hospitalization, confirming Lyme disease.
Lyme disease is a vector-borne disease caused by the Borrelia genus of spirochete bacteria, most commonly Borrelia burgdorferi in North America. Transmission occurs through prolonged (typically 36-48 hours) attachment of a blacklegged tick.
The disease can be divided into 3 stages:
- localized (3-30 days): erythema migrans rash and flulike illness
- early disseminated (days to weeks; seen in this patient): multiple erythema migrans rashes, early neuroborreliosis, arthritis, carditis, and rarely hepatitis and uveitis
- late disseminated (months to years): chronic Lyme arthritis, chronic neurological disorders (eg, encephalopathy, radicular pain, and chronic neuropathy).
The initial erythema migrans rash is classically red and targetoid; it expands from the site of attachment. Early disseminated patches tend to be smaller and can occur on any body part. The rash is rarely itchy or painful but may be warm to the touch or sensitive. The rash resolves spontaneously within 3 to 4 weeks of onset.
Treatment of all early and early disseminated Lyme disease typically involves a 14- to 28-day course of doxycycline (100 mg bid for adults, 2.2 mg/kg bid [maximum 100 mg bid] for children). Patients with acute neurologic disease often can be treated with doxycycline, but patients who cannot tolerate doxycycline and those with parenchymal disease such as encephalitis should receive IV therapy with ceftriaxone 2 g/d.
In this case, the patient was discharged home on a 3-week course of doxycycline 100 mg bid and cleared without further symptoms.
Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).
Lyme disease. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/lyme/healthcare/index.html. Accessed September 1, 2020.
The constellation of symptoms was suggestive of Lyme disease, although connective tissue disease and syphilis were also considered. Two punch biopsies were performed in the office, and erythrocyte sedimentation rate (ESR), complete blood cell count (CBC), international normalized ratio (INR), comprehensive metabolic panel (CMP), Lyme enzyme-linked immunosorbent assay (ELISA) antibody panel, and rapid plasma reagin (RPR) laboratory tests were ordered.
Immediately available laboratory results included ESR, CBC, INR, and CMP. Findings were notable for elevated INR, as well as elevated alanine aminotransferase and aspartate transaminase. The transaminitis suggested myopathy and was consistent with clinical muscle weakness. RPR testing was negative.
Because of the confusion, severity of muscle weakness, and plausibility of early encephalopathy with Lyme disease, the patient was admitted to the hospital for further work-up. Lumbar puncture was delayed until his INR was reduced, but subsequently was found to be normal. He received intravenous (IV) ceftriaxone (2 g/d) empirically for possible early disseminated disease with neurologic complications. His confusion, muscle weakness, and transaminitis rapidly improved.
His Lyme antibody panel was positive for IgM after his third day of hospitalization. A reflexive confirmatory western blot for IgG was not positive on the initial set of labs but was positive when redrawn 4 weeks after this hospitalization, confirming Lyme disease.
Lyme disease is a vector-borne disease caused by the Borrelia genus of spirochete bacteria, most commonly Borrelia burgdorferi in North America. Transmission occurs through prolonged (typically 36-48 hours) attachment of a blacklegged tick.
The disease can be divided into 3 stages:
- localized (3-30 days): erythema migrans rash and flulike illness
- early disseminated (days to weeks; seen in this patient): multiple erythema migrans rashes, early neuroborreliosis, arthritis, carditis, and rarely hepatitis and uveitis
- late disseminated (months to years): chronic Lyme arthritis, chronic neurological disorders (eg, encephalopathy, radicular pain, and chronic neuropathy).
The initial erythema migrans rash is classically red and targetoid; it expands from the site of attachment. Early disseminated patches tend to be smaller and can occur on any body part. The rash is rarely itchy or painful but may be warm to the touch or sensitive. The rash resolves spontaneously within 3 to 4 weeks of onset.
Treatment of all early and early disseminated Lyme disease typically involves a 14- to 28-day course of doxycycline (100 mg bid for adults, 2.2 mg/kg bid [maximum 100 mg bid] for children). Patients with acute neurologic disease often can be treated with doxycycline, but patients who cannot tolerate doxycycline and those with parenchymal disease such as encephalitis should receive IV therapy with ceftriaxone 2 g/d.
In this case, the patient was discharged home on a 3-week course of doxycycline 100 mg bid and cleared without further symptoms.
Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).
The constellation of symptoms was suggestive of Lyme disease, although connective tissue disease and syphilis were also considered. Two punch biopsies were performed in the office, and erythrocyte sedimentation rate (ESR), complete blood cell count (CBC), international normalized ratio (INR), comprehensive metabolic panel (CMP), Lyme enzyme-linked immunosorbent assay (ELISA) antibody panel, and rapid plasma reagin (RPR) laboratory tests were ordered.
Immediately available laboratory results included ESR, CBC, INR, and CMP. Findings were notable for elevated INR, as well as elevated alanine aminotransferase and aspartate transaminase. The transaminitis suggested myopathy and was consistent with clinical muscle weakness. RPR testing was negative.
Because of the confusion, severity of muscle weakness, and plausibility of early encephalopathy with Lyme disease, the patient was admitted to the hospital for further work-up. Lumbar puncture was delayed until his INR was reduced, but subsequently was found to be normal. He received intravenous (IV) ceftriaxone (2 g/d) empirically for possible early disseminated disease with neurologic complications. His confusion, muscle weakness, and transaminitis rapidly improved.
His Lyme antibody panel was positive for IgM after his third day of hospitalization. A reflexive confirmatory western blot for IgG was not positive on the initial set of labs but was positive when redrawn 4 weeks after this hospitalization, confirming Lyme disease.
Lyme disease is a vector-borne disease caused by the Borrelia genus of spirochete bacteria, most commonly Borrelia burgdorferi in North America. Transmission occurs through prolonged (typically 36-48 hours) attachment of a blacklegged tick.
The disease can be divided into 3 stages:
- localized (3-30 days): erythema migrans rash and flulike illness
- early disseminated (days to weeks; seen in this patient): multiple erythema migrans rashes, early neuroborreliosis, arthritis, carditis, and rarely hepatitis and uveitis
- late disseminated (months to years): chronic Lyme arthritis, chronic neurological disorders (eg, encephalopathy, radicular pain, and chronic neuropathy).
The initial erythema migrans rash is classically red and targetoid; it expands from the site of attachment. Early disseminated patches tend to be smaller and can occur on any body part. The rash is rarely itchy or painful but may be warm to the touch or sensitive. The rash resolves spontaneously within 3 to 4 weeks of onset.
Treatment of all early and early disseminated Lyme disease typically involves a 14- to 28-day course of doxycycline (100 mg bid for adults, 2.2 mg/kg bid [maximum 100 mg bid] for children). Patients with acute neurologic disease often can be treated with doxycycline, but patients who cannot tolerate doxycycline and those with parenchymal disease such as encephalitis should receive IV therapy with ceftriaxone 2 g/d.
In this case, the patient was discharged home on a 3-week course of doxycycline 100 mg bid and cleared without further symptoms.
Text courtesy of Tristan Reynolds, DO, Maine Dartmouth Family Medicine Residency, and Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).
Lyme disease. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/lyme/healthcare/index.html. Accessed September 1, 2020.
Lyme disease. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/lyme/healthcare/index.html. Accessed September 1, 2020.
Study supports multigene panel testing for all breast cancer patients with second primary cancers
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
according to a paper published in JCO Precision Oncology.
The authors noted that women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. However, it hasn’t been clear if mutations in genes other than BRCA1/2 are enriched in patients with multiple primary cancers.
“Surprisingly few papers have focused on genetic evaluation of patients with multiple primary cancers,” senior author Katherine L. Nathanson, MD, of the University of Pennsylvania in Philadelphia, said in an interview.
“Ours is one of the first studies to look closely at this issue. We know from clinical experience that these patients are more likely to have more than one genetic mutation,” she added.
For their study, Dr. Nathanson and colleagues identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in two cohorts.
Cohort 1 consisted of 1,000 high-risk breast cancer patients – 551 with multiple primary cancers and 449 with a single breast cancer.
Cohort 2 included 1,804 familial breast cancer patients – 340 with multiple primaries and 1,464 with a single breast cancer.
The researchers assessed mutations in these cohorts and compared them with mutations in a control data set.
Mutation rates and age
Pathogenic mutation rates were higher in both cohorts in patients with multiple primaries as compared with patients with single primaries.
In cohort 1, the overall panel positive rate was 8.53% in the multiple-primaries group and 4.90% in the single-primary group (P = .024).
In cohort 2, the overall panel positive rate was 7.06% in the multiple-primaries group and 4.23% in the single-primary group (P = .034).
In both cohorts, younger age at first breast cancer was associated with higher mutation rates. However, the age at onset of cancers other than breast cancer was not related to mutation rate.
“Regardless of age, mutations in genes other than BRCA1/2 are found in at least 5% of patients with breast cancer and another primary cancer, with up to 25% in patients with their first breast cancer at age 30 years,” Dr. Nathanson said. “This supports the need for multigene panel testing in all patients with breast cancer and another primary cancer.”
“Once a woman has multiple primaries with breast cancer, it doesn’t matter what her family history is, she is more likely to be at risk,” Dr. Nathanson added.
Genetic susceptibility
The researchers also identified genes associated with multiple primary cancers. TP53 and MSH6 mutations were significantly enriched in patients with multiple primaries but not single primaries. ATM and PALB2 mutations were significantly enriched in both groups when compared with controls.
The researchers noted that high-penetrance cancer genes were responsible for higher mutation rates in the cohort enriched for early-onset breast cancer and non–breast cancer second primaries. Moderate-penetrance cancer genes were responsible for the higher mutation rates in the cohort enriched for familial breast cancer and second breast cancer primaries.
“In multiple primary cancers, we found additional genes with moderate penetrance and some genes with high penetrance associated with TP53 and Lynch syndrome,” Dr. Nathanson said.
Cancer prevention and screening
The results of this study could lead to better implementation of cancer prevention and screening strategies, according to the researchers.
“As we look at guidelines in development and NCCN recommendations, our data suggest that age should not be part of the criteria for genetic testing in patients who have more than one primary cancer. These patients are at high risk and should be recommended for screening,” Dr. Nathanson said.
“If you see a patient with multiple primary cancers, refer for genetic testing. Age does not matter,” she reiterated.
Future research will look at potentially missing mutations.
“With targeted sequencing, structurally rearranged genes might be missed for those at risk. We will try to identify cancer susceptibility genes and define the true risk of penetrance of these genes in the general population,” Dr. Nathanson said.
This research was supported by grants from government agencies and foundations as well as the University of Pennsylvania. Dr. Nathanson disclosed no conflicts of interest. Other authors disclosed relationships with a range of companies, all listed in the paper.
SOURCE: Maxwell KN et al. JCO Precis Oncol. 2020. doi: 10.1200/PO.19.00301.
FROM JCO PRECISION ONCOLOGY