For almost a quarter century, Julie Powers, a 48-year-old non-profit professional from Maryland, has been taking the same medication for her lupus — and until recently, she never worried that her supply would run out. Now she’s terrified that she might lose access to a drug that prevents her immune system from attacking her heart, lungs, and skin. She describes a feeling akin to being underwater, near drowning: “That’s what my life would be like,” she said. “I’ll suffocate.”

Powers’ concerns began roughly a week ago when she learned that her lupus drug, hydroxychloroquine (hi-DROCK-see-KLORA-quin), may be helpful in the treatment of Covid-19, the illness caused by the SARS-CoV-2 virus now racing across the planet. The medication was already being used around world to treat Covid-19 patients, but evidence of its effectiveness was largely anecdotal. Then, on March 16, a renowned infectious disease specialist, Didier Raoult, announced the results of a small clinical trial in France showing that patients receiving a combination of hydroxychloroquine and the common antibiotic azithromycin had notably lower levels of the virus in their bloodstream than those who did not receive the medication.

In the last week, this once obscure drug has been thrust into the national spotlight with everyone from doctors, to laypeople, to the U.S. president weighing in. The attention has so dramatically driven up demand that pharmacists are reporting depleted stocks of the drug, leaving many of the roughly 1.5 million lupus patients across the country unable to get their prescriptions filled. They now face an uncertain future as the public clings to one of the first signs of hope to appear since the coronavirus began sweeping across the U.S.

But scientists and physicians caution that this hope is based on studies that have been conducted outside of traditional scientific timelines. “The paper is interesting and certainly would warrant future more definitive studies,” Jeff Sparks, a rheumatologist and researcher at Harvard Medical School, said of the French study. “It might even be enough data to use the regimen off-label for sick and hospitalized patients.

“However,” he added, “it does not prove that the regimen actually works.”

Despite efforts to pin blame for the shortages on Trump alone, however, hydroxychloroquine scarcity was already setting in weeks ago, as doctors began responding on their own to percolating and preliminary research. Some evidence suggests that many doctors are now writing prescriptions prophylactically for patients with no known illness — as well as for themselves and family members — prompting at least one state pharmacy board to call an emergency meeting, scheduled for Sunday morning. The board planned to bar pharmacists from dispensing chloroquine or hydroxychloroquine for anyone other than confirmed Covid-19 patients without approval of the board's director.

A prolonged shortfall in supplies would likely have grave implications for people who depend on it — including Powers, who believes that she would not be alive today without the drug. “I guarantee you, it has saved my life,” she said. “It’s the only thing that’s protecting my organs. There’s nothing else.” Like others, she hopes that pharmaceutical companies that manufacture versions of the drug will be able to quickly ramp up production — something several have already promised to do. In the meantime, Powers has a message for the American public — one echoed by most lupus doctors: When it comes to hydroxychloroquine: “If you don’t need it, don’t get it.”

The origins of hydroxychloroquine can be traced back hundreds of years to South America, where the bark of the cinchona tree appears to have been used by Andean populations to treat shivering. European missionaries eventually brought the bark to Europe, where it was used to treat malaria. In 1820, French researchers isolated the substance in the bark responsible for its beneficial effects. They named it “quinine.” When the supply from South America began to dry up, the British and Dutch decided to grow the tree on plantations.

Over time, synthetic versions were developed, including a drug called chloroquine, which was created in the midst of World War II in an effort to spare overseas American troops from malaria. As it turned out, troops with rashes and arthritis saw an improvement in symptoms after using this anti-malarial medication. After the war, a related drug was created, one with fewer side-effects when taken long-term: hydroxychloroquine. It went on to be used to treat many types of autoimmune diseases, including rheumatoid arthritis and lupus. The latter, which disproportionately affects women, used to cut lives short — typically from failure of the kidneys. Those numbers have been reduced with strict management of the disease, but the Lupus Foundation of America estimates that 10 to 15 percent of patients die prematurely due to complications of the disease.

For almost a quarter century, Julie Powers, a 48-year-old non-profit professional from Maryland, has been taking the same medication for her lupus — and until recently, she never worried that her supply would run out. Now she’s terrified that she might lose access to a drug that prevents her immune system from attacking her heart, lungs, and skin. She describes a feeling akin to being underwater, near drowning: “That’s what my life would be like,” she said. “I’ll suffocate.”

Powers’ concerns began roughly a week ago when she learned that her lupus drug, hydroxychloroquine (hi-DROCK-see-KLORA-quin), may be helpful in the treatment of Covid-19, the illness caused by the SARS-CoV-2 virus now racing across the planet. The medication was already being used around world to treat Covid-19 patients, but evidence of its effectiveness was largely anecdotal. Then, on March 16, a renowned infectious disease specialist, Didier Raoult, announced the results of a small clinical trial in France showing that patients receiving a combination of hydroxychloroquine and the common antibiotic azithromycin had notably lower levels of the virus in their bloodstream than those who did not receive the medication.

In the last week, this once obscure drug has been thrust into the national spotlight with everyone from doctors, to laypeople, to the U.S. president weighing in. The attention has so dramatically driven up demand that pharmacists are reporting depleted stocks of the drug, leaving many of the roughly 1.5 million lupus patients across the country unable to get their prescriptions filled. They now face an uncertain future as the public clings to one of the first signs of hope to appear since the coronavirus began sweeping across the U.S.

But scientists and physicians caution that this hope is based on studies that have been conducted outside of traditional scientific timelines. “The paper is interesting and certainly would warrant future more definitive studies,” Jeff Sparks, a rheumatologist and researcher at Harvard Medical School, said of the French study. “It might even be enough data to use the regimen off-label for sick and hospitalized patients.

“However,” he added, “it does not prove that the regimen actually works.”

Despite efforts to pin blame for the shortages on Trump alone, however, hydroxychloroquine scarcity was already setting in weeks ago, as doctors began responding on their own to percolating and preliminary research. Some evidence suggests that many doctors are now writing prescriptions prophylactically for patients with no known illness — as well as for themselves and family members — prompting at least one state pharmacy board to call an emergency meeting, scheduled for Sunday morning. The board planned to bar pharmacists from dispensing chloroquine or hydroxychloroquine for anyone other than confirmed Covid-19 patients without approval of the board's director.

A prolonged shortfall in supplies would likely have grave implications for people who depend on it — including Powers, who believes that she would not be alive today without the drug. “I guarantee you, it has saved my life,” she said. “It’s the only thing that’s protecting my organs. There’s nothing else.” Like others, she hopes that pharmaceutical companies that manufacture versions of the drug will be able to quickly ramp up production — something several have already promised to do. In the meantime, Powers has a message for the American public — one echoed by most lupus doctors: When it comes to hydroxychloroquine: “If you don’t need it, don’t get it.”

The origins of hydroxychloroquine can be traced back hundreds of years to South America, where the bark of the cinchona tree appears to have been used by Andean populations to treat shivering. European missionaries eventually brought the bark to Europe, where it was used to treat malaria. In 1820, French researchers isolated the substance in the bark responsible for its beneficial effects. They named it “quinine.” When the supply from South America began to dry up, the British and Dutch decided to grow the tree on plantations.

Over time, synthetic versions were developed, including a drug called chloroquine, which was created in the midst of World War II in an effort to spare overseas American troops from malaria. As it turned out, troops with rashes and arthritis saw an improvement in symptoms after using this anti-malarial medication. After the war, a related drug was created, one with fewer side-effects when taken long-term: hydroxychloroquine. It went on to be used to treat many types of autoimmune diseases, including rheumatoid arthritis and lupus. The latter, which disproportionately affects women, used to cut lives short — typically from failure of the kidneys. Those numbers have been reduced with strict management of the disease, but the Lupus Foundation of America estimates that 10 to 15 percent of patients die prematurely due to complications of the disease.

For almost a quarter century, Julie Powers, a 48-year-old non-profit professional from Maryland, has been taking the same medication for her lupus — and until recently, she never worried that her supply would run out. Now she’s terrified that she might lose access to a drug that prevents her immune system from attacking her heart, lungs, and skin. She describes a feeling akin to being underwater, near drowning: “That’s what my life would be like,” she said. “I’ll suffocate.”

Powers’ concerns began roughly a week ago when she learned that her lupus drug, hydroxychloroquine (hi-DROCK-see-KLORA-quin), may be helpful in the treatment of Covid-19, the illness caused by the SARS-CoV-2 virus now racing across the planet. The medication was already being used around world to treat Covid-19 patients, but evidence of its effectiveness was largely anecdotal. Then, on March 16, a renowned infectious disease specialist, Didier Raoult, announced the results of a small clinical trial in France showing that patients receiving a combination of hydroxychloroquine and the common antibiotic azithromycin had notably lower levels of the virus in their bloodstream than those who did not receive the medication.

In the last week, this once obscure drug has been thrust into the national spotlight with everyone from doctors, to laypeople, to the U.S. president weighing in. The attention has so dramatically driven up demand that pharmacists are reporting depleted stocks of the drug, leaving many of the roughly 1.5 million lupus patients across the country unable to get their prescriptions filled. They now face an uncertain future as the public clings to one of the first signs of hope to appear since the coronavirus began sweeping across the U.S.

But scientists and physicians caution that this hope is based on studies that have been conducted outside of traditional scientific timelines. “The paper is interesting and certainly would warrant future more definitive studies,” Jeff Sparks, a rheumatologist and researcher at Harvard Medical School, said of the French study. “It might even be enough data to use the regimen off-label for sick and hospitalized patients.

“However,” he added, “it does not prove that the regimen actually works.”

Despite efforts to pin blame for the shortages on Trump alone, however, hydroxychloroquine scarcity was already setting in weeks ago, as doctors began responding on their own to percolating and preliminary research. Some evidence suggests that many doctors are now writing prescriptions prophylactically for patients with no known illness — as well as for themselves and family members — prompting at least one state pharmacy board to call an emergency meeting, scheduled for Sunday morning. The board planned to bar pharmacists from dispensing chloroquine or hydroxychloroquine for anyone other than confirmed Covid-19 patients without approval of the board's director.

A prolonged shortfall in supplies would likely have grave implications for people who depend on it — including Powers, who believes that she would not be alive today without the drug. “I guarantee you, it has saved my life,” she said. “It’s the only thing that’s protecting my organs. There’s nothing else.” Like others, she hopes that pharmaceutical companies that manufacture versions of the drug will be able to quickly ramp up production — something several have already promised to do. In the meantime, Powers has a message for the American public — one echoed by most lupus doctors: When it comes to hydroxychloroquine: “If you don’t need it, don’t get it.”

The origins of hydroxychloroquine can be traced back hundreds of years to South America, where the bark of the cinchona tree appears to have been used by Andean populations to treat shivering. European missionaries eventually brought the bark to Europe, where it was used to treat malaria. In 1820, French researchers isolated the substance in the bark responsible for its beneficial effects. They named it “quinine.” When the supply from South America began to dry up, the British and Dutch decided to grow the tree on plantations.

Over time, synthetic versions were developed, including a drug called chloroquine, which was created in the midst of World War II in an effort to spare overseas American troops from malaria. As it turned out, troops with rashes and arthritis saw an improvement in symptoms after using this anti-malarial medication. After the war, a related drug was created, one with fewer side-effects when taken long-term: hydroxychloroquine. It went on to be used to treat many types of autoimmune diseases, including rheumatoid arthritis and lupus. The latter, which disproportionately affects women, used to cut lives short — typically from failure of the kidneys. Those numbers have been reduced with strict management of the disease, but the Lupus Foundation of America estimates that 10 to 15 percent of patients die prematurely due to complications of the disease.

In a webinar conducted on March 20, Leonard Valentino, MD, president and CEO of the National Hemophilia Foundation (NHF), provided specific information of relevance and some reassurance to the bleeding disorders community on the impact of COVID-19.

Overall, the risk of comorbidities is no different in the bleeding disorders population than in the general population, and similar precautions should be maintained, Dr. Valentino stated. He listed some of the at-risk populations as designated by the Centers for Disease Control and Prevention.

In particular, he pointed out that, when the CDC referred to a greater risk of COVID-19 to individuals with bleeding disorders, the organization was referring to patients with HIV and sickle cell disease. The CDC was not referring to patients with other forms of bleeding disorders, such as hemophilia, Dr. Valentino stated.

All individuals should be following CDC and state and federal recommendations with regard to social distancing and hygiene. However, with regard to immunocompromised individuals, “the two populations we [in the bleeding disorders community] have to be concerned about are those in gene therapy clinical trials and those with inhibitors,” said Dr. Valentino.

Patients in a gene therapy clinical trial should exercise additional precautions because the use of steroids, common in these trials. “Steroids are an immunosuppressive drug, and this would increase one’s risk of infection, including COVID-19,” according to Dr. Valentino.

In addition, “I will say, if you have hemophilia and an inhibitor [an antibody to clotting factor treatment], that may alter the immune system, and we don’t know what the implication of that is in terms of coronavirus infection and COVID-19 disease. So people with an inhibitor should take special precautions to limit their exposures.”

Patients with a port should not need to have extra concerns regarding COVID-19, but they should continue to exercise the good hygiene that has always been essential, according to Dr. Valentino.

Dr. Valentino asked: Are patients with a bleeding disorder who become infected with COVID-19 more susceptible to a bleed? “You shouldn’t be more susceptible to bleeding except if you have severe cough, and that cough could result in bleeding to the head,” he answered.

If a patient needs to go to the emergency department for a bleed or possible COVID-19 infection, they should wear a face mask if they are sick to prevent spreading of disease. “This is really the only instance where a face mask may be beneficial” in that it limits other people’s exposure to your infection. It is especially important to call ahead before visiting the doctor or going to the emergency department. “Make sure that they’re aware that you’re coming.”

Of particular concern to patients is the amount of factor product they should have on hand. The current CDC recommendation is a 30-day supply of medicines, but that is misleading, because it refers to general medications, such as high-blood pressure medicine, and not factor products. “The current MASAC [NHF’s Medical and Scientific Advisory Council] recommendation is to have a 14-day supply of factor products available to you,” said Dr. Valentino, “and one should reorder when you have a 1-week supply.”

MASAC has issued a letter on the crisis on the NHF website.

These recommendations should not be exceeded in order to ensure that there is enough factor available to all patients, he added. Hoarding is discouraged, and there are no concerns as yet of factor running out. “We have had conversations with manufacturers and … the supply chain is robust.” The greater concern is with regard to ancillary supplies in the hospital that a hemophilia patient may require during treatment.

Patients and practitioners should consult the COVID-19 pages of both the NHF and Hemophilia Federation of America (HFA) websites. This includes a Health and Wellness update by Dr. Valentino.

With regard to financial issues, he and Sharon Meyers, CEO and president of the HFA, spoke, stating that both NHF and HFA have advocacy for patients seeking to deal with insurance issues or in paying for their products, urging people to go to the organizational websites and to also use their emails: [email protected] and [email protected].

She also announced that the annual meeting of the HFA was being postponed to Aug. 24-26 at the Hilton Inner Harbor Baltimore, Md.

Dr. Valentino and Ms. Meyers did not provide any disclosure information.

[email protected]

In a webinar conducted on March 20, Leonard Valentino, MD, president and CEO of the National Hemophilia Foundation (NHF), provided specific information of relevance and some reassurance to the bleeding disorders community on the impact of COVID-19.

Overall, the risk of comorbidities is no different in the bleeding disorders population than in the general population, and similar precautions should be maintained, Dr. Valentino stated. He listed some of the at-risk populations as designated by the Centers for Disease Control and Prevention.

In particular, he pointed out that, when the CDC referred to a greater risk of COVID-19 to individuals with bleeding disorders, the organization was referring to patients with HIV and sickle cell disease. The CDC was not referring to patients with other forms of bleeding disorders, such as hemophilia, Dr. Valentino stated.

All individuals should be following CDC and state and federal recommendations with regard to social distancing and hygiene. However, with regard to immunocompromised individuals, “the two populations we [in the bleeding disorders community] have to be concerned about are those in gene therapy clinical trials and those with inhibitors,” said Dr. Valentino.

Patients in a gene therapy clinical trial should exercise additional precautions because the use of steroids, common in these trials. “Steroids are an immunosuppressive drug, and this would increase one’s risk of infection, including COVID-19,” according to Dr. Valentino.

In addition, “I will say, if you have hemophilia and an inhibitor [an antibody to clotting factor treatment], that may alter the immune system, and we don’t know what the implication of that is in terms of coronavirus infection and COVID-19 disease. So people with an inhibitor should take special precautions to limit their exposures.”

Patients with a port should not need to have extra concerns regarding COVID-19, but they should continue to exercise the good hygiene that has always been essential, according to Dr. Valentino.

Dr. Valentino asked: Are patients with a bleeding disorder who become infected with COVID-19 more susceptible to a bleed? “You shouldn’t be more susceptible to bleeding except if you have severe cough, and that cough could result in bleeding to the head,” he answered.

If a patient needs to go to the emergency department for a bleed or possible COVID-19 infection, they should wear a face mask if they are sick to prevent spreading of disease. “This is really the only instance where a face mask may be beneficial” in that it limits other people’s exposure to your infection. It is especially important to call ahead before visiting the doctor or going to the emergency department. “Make sure that they’re aware that you’re coming.”

Of particular concern to patients is the amount of factor product they should have on hand. The current CDC recommendation is a 30-day supply of medicines, but that is misleading, because it refers to general medications, such as high-blood pressure medicine, and not factor products. “The current MASAC [NHF’s Medical and Scientific Advisory Council] recommendation is to have a 14-day supply of factor products available to you,” said Dr. Valentino, “and one should reorder when you have a 1-week supply.”

MASAC has issued a letter on the crisis on the NHF website.

These recommendations should not be exceeded in order to ensure that there is enough factor available to all patients, he added. Hoarding is discouraged, and there are no concerns as yet of factor running out. “We have had conversations with manufacturers and … the supply chain is robust.” The greater concern is with regard to ancillary supplies in the hospital that a hemophilia patient may require during treatment.

Patients and practitioners should consult the COVID-19 pages of both the NHF and Hemophilia Federation of America (HFA) websites. This includes a Health and Wellness update by Dr. Valentino.

With regard to financial issues, he and Sharon Meyers, CEO and president of the HFA, spoke, stating that both NHF and HFA have advocacy for patients seeking to deal with insurance issues or in paying for their products, urging people to go to the organizational websites and to also use their emails: [email protected] and [email protected].

She also announced that the annual meeting of the HFA was being postponed to Aug. 24-26 at the Hilton Inner Harbor Baltimore, Md.

Dr. Valentino and Ms. Meyers did not provide any disclosure information.

[email protected]

In a webinar conducted on March 20, Leonard Valentino, MD, president and CEO of the National Hemophilia Foundation (NHF), provided specific information of relevance and some reassurance to the bleeding disorders community on the impact of COVID-19.

Overall, the risk of comorbidities is no different in the bleeding disorders population than in the general population, and similar precautions should be maintained, Dr. Valentino stated. He listed some of the at-risk populations as designated by the Centers for Disease Control and Prevention.

In particular, he pointed out that, when the CDC referred to a greater risk of COVID-19 to individuals with bleeding disorders, the organization was referring to patients with HIV and sickle cell disease. The CDC was not referring to patients with other forms of bleeding disorders, such as hemophilia, Dr. Valentino stated.

All individuals should be following CDC and state and federal recommendations with regard to social distancing and hygiene. However, with regard to immunocompromised individuals, “the two populations we [in the bleeding disorders community] have to be concerned about are those in gene therapy clinical trials and those with inhibitors,” said Dr. Valentino.

Patients in a gene therapy clinical trial should exercise additional precautions because the use of steroids, common in these trials. “Steroids are an immunosuppressive drug, and this would increase one’s risk of infection, including COVID-19,” according to Dr. Valentino.

In addition, “I will say, if you have hemophilia and an inhibitor [an antibody to clotting factor treatment], that may alter the immune system, and we don’t know what the implication of that is in terms of coronavirus infection and COVID-19 disease. So people with an inhibitor should take special precautions to limit their exposures.”

Patients with a port should not need to have extra concerns regarding COVID-19, but they should continue to exercise the good hygiene that has always been essential, according to Dr. Valentino.

Dr. Valentino asked: Are patients with a bleeding disorder who become infected with COVID-19 more susceptible to a bleed? “You shouldn’t be more susceptible to bleeding except if you have severe cough, and that cough could result in bleeding to the head,” he answered.

If a patient needs to go to the emergency department for a bleed or possible COVID-19 infection, they should wear a face mask if they are sick to prevent spreading of disease. “This is really the only instance where a face mask may be beneficial” in that it limits other people’s exposure to your infection. It is especially important to call ahead before visiting the doctor or going to the emergency department. “Make sure that they’re aware that you’re coming.”

Of particular concern to patients is the amount of factor product they should have on hand. The current CDC recommendation is a 30-day supply of medicines, but that is misleading, because it refers to general medications, such as high-blood pressure medicine, and not factor products. “The current MASAC [NHF’s Medical and Scientific Advisory Council] recommendation is to have a 14-day supply of factor products available to you,” said Dr. Valentino, “and one should reorder when you have a 1-week supply.”

MASAC has issued a letter on the crisis on the NHF website.

These recommendations should not be exceeded in order to ensure that there is enough factor available to all patients, he added. Hoarding is discouraged, and there are no concerns as yet of factor running out. “We have had conversations with manufacturers and … the supply chain is robust.” The greater concern is with regard to ancillary supplies in the hospital that a hemophilia patient may require during treatment.

Patients and practitioners should consult the COVID-19 pages of both the NHF and Hemophilia Federation of America (HFA) websites. This includes a Health and Wellness update by Dr. Valentino.

With regard to financial issues, he and Sharon Meyers, CEO and president of the HFA, spoke, stating that both NHF and HFA have advocacy for patients seeking to deal with insurance issues or in paying for their products, urging people to go to the organizational websites and to also use their emails: [email protected] and [email protected].

She also announced that the annual meeting of the HFA was being postponed to Aug. 24-26 at the Hilton Inner Harbor Baltimore, Md.

Dr. Valentino and Ms. Meyers did not provide any disclosure information.

[email protected]

Click to read.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects approximately 10% of US children. Colloidal oatmeal has long been used as a topical treatment for AD and modern research confirms the benefits of colloidal oatmeal formulations to significantly improve symptoms. Click to learn more about colloidal oatmeal in combination with oat flour and oat extract as effective and well-tolerated skin-directed therapy for your young AD patients. 

Click to read. 

About the Author

Click to read.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects approximately 10% of US children. Colloidal oatmeal has long been used as a topical treatment for AD and modern research confirms the benefits of colloidal oatmeal formulations to significantly improve symptoms. Click to learn more about colloidal oatmeal in combination with oat flour and oat extract as effective and well-tolerated skin-directed therapy for your young AD patients. 

Click to read. 

About the Author

Click to read.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects approximately 10% of US children. Colloidal oatmeal has long been used as a topical treatment for AD and modern research confirms the benefits of colloidal oatmeal formulations to significantly improve symptoms. Click to learn more about colloidal oatmeal in combination with oat flour and oat extract as effective and well-tolerated skin-directed therapy for your young AD patients. 

Click to read. 

About the Author

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

Researchers have hypothesized that treatments that increase angiotensin-converting enzyme 2 (ACE2) may also increase the risk of novel coronavirus disease (COVID-19). This speculation and other concerns have led some officials and organizations to question whether ibuprofen or other drugs such as renin angiotensin aldosterone system (RAAS) antagonists should be avoided as treatments in patients with COVID-19. Health agencies and professional organizations have said they are not recommending against these medications.

The Food and Drug Administration on March 19 advised patients that it was “not aware of scientific evidence connecting” nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen “with worsening COVID-19 symptoms.”

“The agency is investigating this issue further and will communicate publicly when more information is available,” the FDA said. “However, all prescription NSAID labels warn that ‘the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.’ ” The FDA also noted that other over-the-counter and prescription medications are available for pain relief and fever reduction, and patients who “are concerned about taking NSAIDs and rely on these medications to treat chronic diseases” should talk to a health care provider.

A World Health Organization spokesperson said during a press conference on March 17 that the organization was looking into concerns about ibuprofen use in patients with COVID-19 and suggested that in the meantime patients take acetaminophen for fever instead. On March 18, the WHO said that it was not recommending against the use of ibuprofen.

“At present, based on currently available information, WHO does not recommend against the use of ibuprofen,” the organization said. “We are also consulting with physicians treating COVID-19 patients and are not aware of reports of any negative effects of ibuprofen, beyond the usual known side effects that limit its use in certain populations. WHO is not aware of published clinical or population-based data on this topic.”

A spokesperson for the National Institute of Allergy and Infectious Diseases said on March 18, “More research is needed to evaluate reports that ibruprofen and other over-the-counter anti-inflammatory drugs may affect the course of COVID-19. Currently, there is no conclusive evidence that ibuprofen and other over-the-counter anti-inflammatory drugs increase the risk of serious complications or of acquiring the virus that causes COVID-19. There is also no conclusive evidence that taking over-the-counter anti-inflammatory drugs is harmful for other respiratory infections.”

The European Medicines Agency (EMA) on March 18 said, “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19. EMA is monitoring the situation closely and will review any new information that becomes available on this issue in the context of the pandemic.”

In correspondence published March 11 in the Lancet Respiratory Medicine, Lei Fang, MD, of the department of biomedicine at University Hospital Basel (Switzerland), and colleagues suggested that patients with hypertension and diabetes mellitus may be at increased risk of COVID-19 because these comorbidities “are often treated with angiotensin converting enzyme (ACE) inhibitors.” In addition, “ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension” also may play a role, the researchers said (Lancet Respir Med. 2020 Mar 11. https://doi.org/10.1016/S2213-2600(20)30116-8).

“ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.”

A March 16 statement from the Heart Failure Society of America (HSFC), American College of Cardiology (ACC), and American Heart Association (AHA) addressed concerns about using RAAS antagonists in COVID-19.

“Patients with underlying cardiovascular diseases appear to have an increased risk for adverse outcomes with [COVID-19],” the organizations said. “Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients also may have severe cardiovascular damage. [ACE2] receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both [ACE] inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart. Though these have not been shown in human studies, or in the setting of COVID-19, such potential upregulation of ACE2 by ACE inhibitors or ARBs has resulted in a speculation of potential increased risk for COVID-19 infection in patients with background treatment of these medications.”

ACE2, ACE, angiotensin II, and other RAAS system interactions “are quite complex, and at times, paradoxical,” the statement says. “In experimental studies, both ACE inhibitors and ARBs have been shown to reduce severe lung injury in certain viral pneumonias, and it has been speculated that these agents could be beneficial in COVID-19.

“Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents. The HFSA, ACC, and AHA recommend continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease. In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation. Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice.

“These theoretical concerns and findings of cardiovascular involvement with COVID-19 deserve much more detailed research, and quickly. As further research and developments related to this issue evolve, we will update these recommendations as needed.”

Dr. Fang and colleagues had no competing interests.
 

[email protected]

SOURCE: Fang L et al. Lancet Respir Med. 2020 Mar 11. doi: 10.1016/S2213-2600(20)30116-8.

Researchers have hypothesized that treatments that increase angiotensin-converting enzyme 2 (ACE2) may also increase the risk of novel coronavirus disease (COVID-19). This speculation and other concerns have led some officials and organizations to question whether ibuprofen or other drugs such as renin angiotensin aldosterone system (RAAS) antagonists should be avoided as treatments in patients with COVID-19. Health agencies and professional organizations have said they are not recommending against these medications.

The Food and Drug Administration on March 19 advised patients that it was “not aware of scientific evidence connecting” nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen “with worsening COVID-19 symptoms.”

“The agency is investigating this issue further and will communicate publicly when more information is available,” the FDA said. “However, all prescription NSAID labels warn that ‘the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.’ ” The FDA also noted that other over-the-counter and prescription medications are available for pain relief and fever reduction, and patients who “are concerned about taking NSAIDs and rely on these medications to treat chronic diseases” should talk to a health care provider.

A World Health Organization spokesperson said during a press conference on March 17 that the organization was looking into concerns about ibuprofen use in patients with COVID-19 and suggested that in the meantime patients take acetaminophen for fever instead. On March 18, the WHO said that it was not recommending against the use of ibuprofen.

“At present, based on currently available information, WHO does not recommend against the use of ibuprofen,” the organization said. “We are also consulting with physicians treating COVID-19 patients and are not aware of reports of any negative effects of ibuprofen, beyond the usual known side effects that limit its use in certain populations. WHO is not aware of published clinical or population-based data on this topic.”

A spokesperson for the National Institute of Allergy and Infectious Diseases said on March 18, “More research is needed to evaluate reports that ibruprofen and other over-the-counter anti-inflammatory drugs may affect the course of COVID-19. Currently, there is no conclusive evidence that ibuprofen and other over-the-counter anti-inflammatory drugs increase the risk of serious complications or of acquiring the virus that causes COVID-19. There is also no conclusive evidence that taking over-the-counter anti-inflammatory drugs is harmful for other respiratory infections.”

The European Medicines Agency (EMA) on March 18 said, “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19. EMA is monitoring the situation closely and will review any new information that becomes available on this issue in the context of the pandemic.”

In correspondence published March 11 in the Lancet Respiratory Medicine, Lei Fang, MD, of the department of biomedicine at University Hospital Basel (Switzerland), and colleagues suggested that patients with hypertension and diabetes mellitus may be at increased risk of COVID-19 because these comorbidities “are often treated with angiotensin converting enzyme (ACE) inhibitors.” In addition, “ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension” also may play a role, the researchers said (Lancet Respir Med. 2020 Mar 11. https://doi.org/10.1016/S2213-2600(20)30116-8).

“ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.”

A March 16 statement from the Heart Failure Society of America (HSFC), American College of Cardiology (ACC), and American Heart Association (AHA) addressed concerns about using RAAS antagonists in COVID-19.

“Patients with underlying cardiovascular diseases appear to have an increased risk for adverse outcomes with [COVID-19],” the organizations said. “Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients also may have severe cardiovascular damage. [ACE2] receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both [ACE] inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart. Though these have not been shown in human studies, or in the setting of COVID-19, such potential upregulation of ACE2 by ACE inhibitors or ARBs has resulted in a speculation of potential increased risk for COVID-19 infection in patients with background treatment of these medications.”

ACE2, ACE, angiotensin II, and other RAAS system interactions “are quite complex, and at times, paradoxical,” the statement says. “In experimental studies, both ACE inhibitors and ARBs have been shown to reduce severe lung injury in certain viral pneumonias, and it has been speculated that these agents could be beneficial in COVID-19.

“Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents. The HFSA, ACC, and AHA recommend continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease. In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation. Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice.

“These theoretical concerns and findings of cardiovascular involvement with COVID-19 deserve much more detailed research, and quickly. As further research and developments related to this issue evolve, we will update these recommendations as needed.”

Dr. Fang and colleagues had no competing interests.
 

[email protected]

SOURCE: Fang L et al. Lancet Respir Med. 2020 Mar 11. doi: 10.1016/S2213-2600(20)30116-8.

Researchers have hypothesized that treatments that increase angiotensin-converting enzyme 2 (ACE2) may also increase the risk of novel coronavirus disease (COVID-19). This speculation and other concerns have led some officials and organizations to question whether ibuprofen or other drugs such as renin angiotensin aldosterone system (RAAS) antagonists should be avoided as treatments in patients with COVID-19. Health agencies and professional organizations have said they are not recommending against these medications.

The Food and Drug Administration on March 19 advised patients that it was “not aware of scientific evidence connecting” nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen “with worsening COVID-19 symptoms.”

“The agency is investigating this issue further and will communicate publicly when more information is available,” the FDA said. “However, all prescription NSAID labels warn that ‘the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.’ ” The FDA also noted that other over-the-counter and prescription medications are available for pain relief and fever reduction, and patients who “are concerned about taking NSAIDs and rely on these medications to treat chronic diseases” should talk to a health care provider.

A World Health Organization spokesperson said during a press conference on March 17 that the organization was looking into concerns about ibuprofen use in patients with COVID-19 and suggested that in the meantime patients take acetaminophen for fever instead. On March 18, the WHO said that it was not recommending against the use of ibuprofen.

“At present, based on currently available information, WHO does not recommend against the use of ibuprofen,” the organization said. “We are also consulting with physicians treating COVID-19 patients and are not aware of reports of any negative effects of ibuprofen, beyond the usual known side effects that limit its use in certain populations. WHO is not aware of published clinical or population-based data on this topic.”

A spokesperson for the National Institute of Allergy and Infectious Diseases said on March 18, “More research is needed to evaluate reports that ibruprofen and other over-the-counter anti-inflammatory drugs may affect the course of COVID-19. Currently, there is no conclusive evidence that ibuprofen and other over-the-counter anti-inflammatory drugs increase the risk of serious complications or of acquiring the virus that causes COVID-19. There is also no conclusive evidence that taking over-the-counter anti-inflammatory drugs is harmful for other respiratory infections.”

The European Medicines Agency (EMA) on March 18 said, “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19. EMA is monitoring the situation closely and will review any new information that becomes available on this issue in the context of the pandemic.”

In correspondence published March 11 in the Lancet Respiratory Medicine, Lei Fang, MD, of the department of biomedicine at University Hospital Basel (Switzerland), and colleagues suggested that patients with hypertension and diabetes mellitus may be at increased risk of COVID-19 because these comorbidities “are often treated with angiotensin converting enzyme (ACE) inhibitors.” In addition, “ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension” also may play a role, the researchers said (Lancet Respir Med. 2020 Mar 11. https://doi.org/10.1016/S2213-2600(20)30116-8).

“ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.”

A March 16 statement from the Heart Failure Society of America (HSFC), American College of Cardiology (ACC), and American Heart Association (AHA) addressed concerns about using RAAS antagonists in COVID-19.

“Patients with underlying cardiovascular diseases appear to have an increased risk for adverse outcomes with [COVID-19],” the organizations said. “Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients also may have severe cardiovascular damage. [ACE2] receptors have been shown to be the entry point into human cells for SARS-CoV-2, the virus that causes COVID-19. In a few experimental studies with animal models, both [ACE] inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart. Though these have not been shown in human studies, or in the setting of COVID-19, such potential upregulation of ACE2 by ACE inhibitors or ARBs has resulted in a speculation of potential increased risk for COVID-19 infection in patients with background treatment of these medications.”

ACE2, ACE, angiotensin II, and other RAAS system interactions “are quite complex, and at times, paradoxical,” the statement says. “In experimental studies, both ACE inhibitors and ARBs have been shown to reduce severe lung injury in certain viral pneumonias, and it has been speculated that these agents could be beneficial in COVID-19.

“Currently there are no experimental or clinical data demonstrating beneficial or adverse outcomes with background use of ACE inhibitors, ARBs or other RAAS antagonists in COVID-19 or among COVID-19 patients with a history of cardiovascular disease treated with such agents. The HFSA, ACC, and AHA recommend continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease. In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation. Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice.

“These theoretical concerns and findings of cardiovascular involvement with COVID-19 deserve much more detailed research, and quickly. As further research and developments related to this issue evolve, we will update these recommendations as needed.”

Dr. Fang and colleagues had no competing interests.
 

[email protected]

SOURCE: Fang L et al. Lancet Respir Med. 2020 Mar 11. doi: 10.1016/S2213-2600(20)30116-8.

PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.

Doug Brunk/MDedge News

“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”

Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”

Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.

The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.

However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.

Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.

The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”

“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.

In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”

Dr. Pandey reported having no disclosures.

[email protected]

SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.

PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.

Doug Brunk/MDedge News

“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”

Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”

Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.

The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.

However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.

Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.

The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”

“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.

In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”

Dr. Pandey reported having no disclosures.

[email protected]

SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.

PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.

Doug Brunk/MDedge News

“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”

Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”

Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.

The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.

However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.

Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.

The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”

“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.

In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”

Dr. Pandey reported having no disclosures.

[email protected]

SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.

Robert Wachter, MD, MHM, chair of the department of medicine at UCSF, interviewed Armond Esmaili, MD, a hospitalist and assistant professor of medicine at UCSF, who is the leader of the Respiratory Isolation Unit at UCSF Medical Center, where the institution's COVID-19 and rule-out COVID-19 patients are being cohorted.

Robert Wachter, MD, MHM, chair of the department of medicine at UCSF, interviewed Armond Esmaili, MD, a hospitalist and assistant professor of medicine at UCSF, who is the leader of the Respiratory Isolation Unit at UCSF Medical Center, where the institution's COVID-19 and rule-out COVID-19 patients are being cohorted.

Robert Wachter, MD, MHM, chair of the department of medicine at UCSF, interviewed Armond Esmaili, MD, a hospitalist and assistant professor of medicine at UCSF, who is the leader of the Respiratory Isolation Unit at UCSF Medical Center, where the institution's COVID-19 and rule-out COVID-19 patients are being cohorted.

The viral tsunami that is COVID-19 has hit the United States, and influenza appears to be riding the crest of the wave.

Flu activity, in the form of visits to health care providers, increased for the second consecutive week after declining for the three previous weeks, according to the Centers for Disease Control. Flu-related visits went from 5.2% of all outpatient visits the week before to 5.8% during the week ending March 14.

“The COVID-19 outbreak unfolding in the United States may affect healthcare seeking behavior which in turn would impact data from” the U.S. Outpatient Influenza-like Illness Surveillance Network, the CDC explained.

Data from clinical laboratories show that, despite the increased activity, fewer respiratory specimens tested positive for influenza: 15.3% for the week of March 8-14, compared with 21.1% the week before, the CDC’s influenza division said in its latest FluView report.

Influenza activity also increased slightly among the states, with 35 states and Puerto Rico at the highest level on the CDC’s 1-10 scale, versus 34 states and Puerto Rico the previous week. The count was down to 33 for the last week of February, CDC data show.

Severity measures remain mixed as overall hospitalization continues to be moderate but rates for children aged 0-4 years and adults aged 18-49 years are the highest on record and rates for children aged 5-17 years are the highest since the 2009 pandemic, the influenza division said.

Mortality data present a similar picture: The overall death rate is low, but the 149 flu-related deaths reported among children is the most for this point of the season since 2009, the CDC said.

[email protected]

The viral tsunami that is COVID-19 has hit the United States, and influenza appears to be riding the crest of the wave.

Flu activity, in the form of visits to health care providers, increased for the second consecutive week after declining for the three previous weeks, according to the Centers for Disease Control. Flu-related visits went from 5.2% of all outpatient visits the week before to 5.8% during the week ending March 14.

“The COVID-19 outbreak unfolding in the United States may affect healthcare seeking behavior which in turn would impact data from” the U.S. Outpatient Influenza-like Illness Surveillance Network, the CDC explained.

Data from clinical laboratories show that, despite the increased activity, fewer respiratory specimens tested positive for influenza: 15.3% for the week of March 8-14, compared with 21.1% the week before, the CDC’s influenza division said in its latest FluView report.

Influenza activity also increased slightly among the states, with 35 states and Puerto Rico at the highest level on the CDC’s 1-10 scale, versus 34 states and Puerto Rico the previous week. The count was down to 33 for the last week of February, CDC data show.

Severity measures remain mixed as overall hospitalization continues to be moderate but rates for children aged 0-4 years and adults aged 18-49 years are the highest on record and rates for children aged 5-17 years are the highest since the 2009 pandemic, the influenza division said.

Mortality data present a similar picture: The overall death rate is low, but the 149 flu-related deaths reported among children is the most for this point of the season since 2009, the CDC said.

[email protected]

The viral tsunami that is COVID-19 has hit the United States, and influenza appears to be riding the crest of the wave.

Flu activity, in the form of visits to health care providers, increased for the second consecutive week after declining for the three previous weeks, according to the Centers for Disease Control. Flu-related visits went from 5.2% of all outpatient visits the week before to 5.8% during the week ending March 14.

“The COVID-19 outbreak unfolding in the United States may affect healthcare seeking behavior which in turn would impact data from” the U.S. Outpatient Influenza-like Illness Surveillance Network, the CDC explained.

Data from clinical laboratories show that, despite the increased activity, fewer respiratory specimens tested positive for influenza: 15.3% for the week of March 8-14, compared with 21.1% the week before, the CDC’s influenza division said in its latest FluView report.

Influenza activity also increased slightly among the states, with 35 states and Puerto Rico at the highest level on the CDC’s 1-10 scale, versus 34 states and Puerto Rico the previous week. The count was down to 33 for the last week of February, CDC data show.

Severity measures remain mixed as overall hospitalization continues to be moderate but rates for children aged 0-4 years and adults aged 18-49 years are the highest on record and rates for children aged 5-17 years are the highest since the 2009 pandemic, the influenza division said.

Mortality data present a similar picture: The overall death rate is low, but the 149 flu-related deaths reported among children is the most for this point of the season since 2009, the CDC said.

[email protected]

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³