NEW YORK - Shari Cayle, 75, called "Miracle Mama" by her family ever since she beat back advanced colon cancer seven years ago, is still undergoing treatment and living alone.

"I don't want my grandchildren to remember me as the sick one, I want to be the fun one," said Cayle, who is testing a device that passively monitors her activity. "My family knows what I'm doing and I don't think they should have to change their life around to make sure I'm OK."

Onkol, a product inspired by Cayle that monitors her front door, reminds her when to take her medication and can alert her family if she falls, has allowed her to remain independent at home. Devised by her son Marc, it will hit the U.S. market next year.

As more American seniors plan to remain at home rather than enter a nursing facility, new startups and some well-known technology brands are connecting them to family and healthcare providers.

The noninvasive devices sit in the background as users go about their normal routine. Through Bluetooth technology they are able to gather information and send it to family or doctors when, for example, a sensor reads that a pill box was opened or a wireless medical device such as a glucose monitor is used.

According to PricewaterhouseCoopers' Health Research Institute, at-home options like these will disrupt roughly $64 billion of traditional U.S. provider revenue in the next 20 years.

Monitoring devices for the elderly started with products like privately-held Life Alert, which leapt into public awareness nearly 30 years ago with TV ads showing the elderly "Mrs. Fletcher" reaching for her Life Alert pendant and telling an operator, "I've fallen and I can't get up!"

Now companies like Nortek Security & Control and small startups are taking that much further.

The challenge though is that older consumers may not be ready to use the technology and their medical, security and wellness needs may differ significantly. There are also safety and privacy risks.

"There's a lot of potential, but a big gap between what seniors want and what the market can provide," said Harry Wang, director of health and mobile product research at Parks Associates.

NURSE MOLLY

Milwaukee-based Onkol developed a rectangular hub, roughly the size of a tissue box, that passively monitors things like what their blood glucose reading is and when they open their refrigerator. There is also a wristband that can be pressed for help in an emergency.

"The advantage of it is that the person, the patient, doesn't have to worry about hooking it up and doing stuff with the computer, their kids do that," said Cayle, whose son co-founded Onkol.

Sensely is another device used by providers like Kaiser Permanente, based in California, and the National Health Service in the United Kingdom. Since 2013, its virtual nurse Molly has connected patients with doctors from a mobile device. She asks how they are feeling and lets them know when it is time to take a health reading.

Another startup, San Francisco-based Lively began selling its product to consumers in 2012. Similarly, it collects information from sensors and connects to a smart watch that tracks customers' footsteps, routine and can even call emergency services. Next year it will connect with medical devices, send data to physicians and enable video consultations that can replace some doctor's appointments.

Venture firms including Fenox Venture Capital, Maveron, Capital Midwest Fund and LaunchPad Digital Health have contributed millions of dollars to these startups.

Ideal Life, founded in 2002, which sells it own devices to providers, plans to release its own consumer version next year.

"The clinical community is more open than they've even been before in piloting and testing new technology," said founder Jason Goldberg.

Just this summer, Nortek bought a personal emergency response system called Libris and a healthcare platform from Numera, a health technology company, for $12 million. At the same time, Nortek said some of its smart home customers like ADT Corp want to expand into health and wellness offerings. The goal is to offer software that connects with customers' current systems as well as medical, fitness, emergency and security devices.

"In the smart home and health space today you see a lot of single purpose solutions that don't offer a full connectivity platform, like a smart watch or pressure sensor in a bed," said Mike O'Neal, Nortek Security & Control president. "We're creating that connectivity."

A July study from AARP showed Americans 50 years and older want activity monitors like Fitbit and Jawbone to have more relevant sensors to monitor health conditions and 89% cited difficulties with set up.

"They (companies) have great technology, but when you can't open the package or you can't find directions that's a problem," said Jody Holtzman, senior vice president of thought leadership at AARP.

Such products may help doctors keep up with a growing elderly population. Research firm Gartner estimates that in the next 40 years, one-third of the population in developed countries will be 65 years or older, thus making it impossible to keep everyone who needs care in the hospital.

NEW YORK - Shari Cayle, 75, called "Miracle Mama" by her family ever since she beat back advanced colon cancer seven years ago, is still undergoing treatment and living alone.

"I don't want my grandchildren to remember me as the sick one, I want to be the fun one," said Cayle, who is testing a device that passively monitors her activity. "My family knows what I'm doing and I don't think they should have to change their life around to make sure I'm OK."

Onkol, a product inspired by Cayle that monitors her front door, reminds her when to take her medication and can alert her family if she falls, has allowed her to remain independent at home. Devised by her son Marc, it will hit the U.S. market next year.

As more American seniors plan to remain at home rather than enter a nursing facility, new startups and some well-known technology brands are connecting them to family and healthcare providers.

The noninvasive devices sit in the background as users go about their normal routine. Through Bluetooth technology they are able to gather information and send it to family or doctors when, for example, a sensor reads that a pill box was opened or a wireless medical device such as a glucose monitor is used.

According to PricewaterhouseCoopers' Health Research Institute, at-home options like these will disrupt roughly $64 billion of traditional U.S. provider revenue in the next 20 years.

Monitoring devices for the elderly started with products like privately-held Life Alert, which leapt into public awareness nearly 30 years ago with TV ads showing the elderly "Mrs. Fletcher" reaching for her Life Alert pendant and telling an operator, "I've fallen and I can't get up!"

Now companies like Nortek Security & Control and small startups are taking that much further.

The challenge though is that older consumers may not be ready to use the technology and their medical, security and wellness needs may differ significantly. There are also safety and privacy risks.

"There's a lot of potential, but a big gap between what seniors want and what the market can provide," said Harry Wang, director of health and mobile product research at Parks Associates.

NURSE MOLLY

Milwaukee-based Onkol developed a rectangular hub, roughly the size of a tissue box, that passively monitors things like what their blood glucose reading is and when they open their refrigerator. There is also a wristband that can be pressed for help in an emergency.

"The advantage of it is that the person, the patient, doesn't have to worry about hooking it up and doing stuff with the computer, their kids do that," said Cayle, whose son co-founded Onkol.

Sensely is another device used by providers like Kaiser Permanente, based in California, and the National Health Service in the United Kingdom. Since 2013, its virtual nurse Molly has connected patients with doctors from a mobile device. She asks how they are feeling and lets them know when it is time to take a health reading.

Another startup, San Francisco-based Lively began selling its product to consumers in 2012. Similarly, it collects information from sensors and connects to a smart watch that tracks customers' footsteps, routine and can even call emergency services. Next year it will connect with medical devices, send data to physicians and enable video consultations that can replace some doctor's appointments.

Venture firms including Fenox Venture Capital, Maveron, Capital Midwest Fund and LaunchPad Digital Health have contributed millions of dollars to these startups.

Ideal Life, founded in 2002, which sells it own devices to providers, plans to release its own consumer version next year.

"The clinical community is more open than they've even been before in piloting and testing new technology," said founder Jason Goldberg.

Just this summer, Nortek bought a personal emergency response system called Libris and a healthcare platform from Numera, a health technology company, for $12 million. At the same time, Nortek said some of its smart home customers like ADT Corp want to expand into health and wellness offerings. The goal is to offer software that connects with customers' current systems as well as medical, fitness, emergency and security devices.

"In the smart home and health space today you see a lot of single purpose solutions that don't offer a full connectivity platform, like a smart watch or pressure sensor in a bed," said Mike O'Neal, Nortek Security & Control president. "We're creating that connectivity."

A July study from AARP showed Americans 50 years and older want activity monitors like Fitbit and Jawbone to have more relevant sensors to monitor health conditions and 89% cited difficulties with set up.

"They (companies) have great technology, but when you can't open the package or you can't find directions that's a problem," said Jody Holtzman, senior vice president of thought leadership at AARP.

Such products may help doctors keep up with a growing elderly population. Research firm Gartner estimates that in the next 40 years, one-third of the population in developed countries will be 65 years or older, thus making it impossible to keep everyone who needs care in the hospital.

NEW YORK - Shari Cayle, 75, called "Miracle Mama" by her family ever since she beat back advanced colon cancer seven years ago, is still undergoing treatment and living alone.

"I don't want my grandchildren to remember me as the sick one, I want to be the fun one," said Cayle, who is testing a device that passively monitors her activity. "My family knows what I'm doing and I don't think they should have to change their life around to make sure I'm OK."

Onkol, a product inspired by Cayle that monitors her front door, reminds her when to take her medication and can alert her family if she falls, has allowed her to remain independent at home. Devised by her son Marc, it will hit the U.S. market next year.

As more American seniors plan to remain at home rather than enter a nursing facility, new startups and some well-known technology brands are connecting them to family and healthcare providers.

The noninvasive devices sit in the background as users go about their normal routine. Through Bluetooth technology they are able to gather information and send it to family or doctors when, for example, a sensor reads that a pill box was opened or a wireless medical device such as a glucose monitor is used.

According to PricewaterhouseCoopers' Health Research Institute, at-home options like these will disrupt roughly $64 billion of traditional U.S. provider revenue in the next 20 years.

Monitoring devices for the elderly started with products like privately-held Life Alert, which leapt into public awareness nearly 30 years ago with TV ads showing the elderly "Mrs. Fletcher" reaching for her Life Alert pendant and telling an operator, "I've fallen and I can't get up!"

Now companies like Nortek Security & Control and small startups are taking that much further.

The challenge though is that older consumers may not be ready to use the technology and their medical, security and wellness needs may differ significantly. There are also safety and privacy risks.

"There's a lot of potential, but a big gap between what seniors want and what the market can provide," said Harry Wang, director of health and mobile product research at Parks Associates.

NURSE MOLLY

Milwaukee-based Onkol developed a rectangular hub, roughly the size of a tissue box, that passively monitors things like what their blood glucose reading is and when they open their refrigerator. There is also a wristband that can be pressed for help in an emergency.

"The advantage of it is that the person, the patient, doesn't have to worry about hooking it up and doing stuff with the computer, their kids do that," said Cayle, whose son co-founded Onkol.

Sensely is another device used by providers like Kaiser Permanente, based in California, and the National Health Service in the United Kingdom. Since 2013, its virtual nurse Molly has connected patients with doctors from a mobile device. She asks how they are feeling and lets them know when it is time to take a health reading.

Another startup, San Francisco-based Lively began selling its product to consumers in 2012. Similarly, it collects information from sensors and connects to a smart watch that tracks customers' footsteps, routine and can even call emergency services. Next year it will connect with medical devices, send data to physicians and enable video consultations that can replace some doctor's appointments.

Venture firms including Fenox Venture Capital, Maveron, Capital Midwest Fund and LaunchPad Digital Health have contributed millions of dollars to these startups.

Ideal Life, founded in 2002, which sells it own devices to providers, plans to release its own consumer version next year.

"The clinical community is more open than they've even been before in piloting and testing new technology," said founder Jason Goldberg.

Just this summer, Nortek bought a personal emergency response system called Libris and a healthcare platform from Numera, a health technology company, for $12 million. At the same time, Nortek said some of its smart home customers like ADT Corp want to expand into health and wellness offerings. The goal is to offer software that connects with customers' current systems as well as medical, fitness, emergency and security devices.

"In the smart home and health space today you see a lot of single purpose solutions that don't offer a full connectivity platform, like a smart watch or pressure sensor in a bed," said Mike O'Neal, Nortek Security & Control president. "We're creating that connectivity."

A July study from AARP showed Americans 50 years and older want activity monitors like Fitbit and Jawbone to have more relevant sensors to monitor health conditions and 89% cited difficulties with set up.

"They (companies) have great technology, but when you can't open the package or you can't find directions that's a problem," said Jody Holtzman, senior vice president of thought leadership at AARP.

Such products may help doctors keep up with a growing elderly population. Research firm Gartner estimates that in the next 40 years, one-third of the population in developed countries will be 65 years or older, thus making it impossible to keep everyone who needs care in the hospital.

Crowded street

Photo by Pavel Novak

VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.

They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.

“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.

“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”

Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.

They presented this research at the 2015 European Cancer Congress (abstract 1414).

Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.

The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.

There were 5 different subtypes of HL in this group:

• 247 cases of the NS type
• 143 NOS
• 105 of mixed cellularity
• 58 lymphocyte-rich cases
• 68 “others.”

Age and sex

Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.

For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.

“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . .  influencing key genes, induced by sex hormones, may be responsible.”

Overcrowding

The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.

They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).

For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.

Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.

“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”

“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”

Crowded street

Photo by Pavel Novak

VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.

They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.

“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.

“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”

Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.

They presented this research at the 2015 European Cancer Congress (abstract 1414).

Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.

The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.

There were 5 different subtypes of HL in this group:

• 247 cases of the NS type
• 143 NOS
• 105 of mixed cellularity
• 58 lymphocyte-rich cases
• 68 “others.”

Age and sex

Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.

For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.

“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . .  influencing key genes, induced by sex hormones, may be responsible.”

Overcrowding

The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.

They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).

For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.

Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.

“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”

“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”

Crowded street

Photo by Pavel Novak

VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.

They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.

“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.

“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”

Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.

They presented this research at the 2015 European Cancer Congress (abstract 1414).

Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.

The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.

There were 5 different subtypes of HL in this group:

• 247 cases of the NS type
• 143 NOS
• 105 of mixed cellularity
• 58 lymphocyte-rich cases
• 68 “others.”

Age and sex

Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.

For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.

“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . .  influencing key genes, induced by sex hormones, may be responsible.”

Overcrowding

The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.

They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).

For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.

Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.

“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”

“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Children from a village

outside of Nairobi, Kenya

Photo by Gabrielle Tenenbaum

Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.

The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.

The researchers described their findings in a letter to Nature.

“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.

“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”

For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.

They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.

The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.

The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.

The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.

Balancing selection

The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.

This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.

Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.

“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”

Children from a village

outside of Nairobi, Kenya

Photo by Gabrielle Tenenbaum

Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.

The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.

The researchers described their findings in a letter to Nature.

“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.

“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”

For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.

They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.

The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.

The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.

The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.

Balancing selection

The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.

This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.

Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.

“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”

Children from a village

outside of Nairobi, Kenya

Photo by Gabrielle Tenenbaum

Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.

The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.

The researchers described their findings in a letter to Nature.

“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.

“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”

For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.

They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.

The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.

The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.

The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.

Balancing selection

The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.

This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.

Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.

“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”

A 43-year-old man presents for his thyroid checkup. He has known hypothyroidism secondary to Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis. He is taking levothyroxine (LT4) 250 μg (two 125-μg tablets once per day). Review of his prior lab results and notes (see Table 1) reveals frequent dose changes (about every three to six months) and a high dosage of LT4, considering his weight (185 lb).

Patients with little or no residual thyroid function require replacement doses of LT4 at approximately 1.6 μg/kg/d, based on lean body weight.¹ Since the case patient weighs 84 kg, the expected LT4 dosage would be around 125 to 150 μg/d.

This patient requires a significantly higher dose than expected, and his thyroid levels are fluctuating. These facts should trigger further investigation.

Important historical questions I consider when patients have frequent or significant fluctuations in TSH include
• Are you consistent in taking your medication?
• How do you take your thyroid medication?
• Are you taking any iron supplements, vitamins with iron, or contraceptive pills containing iron?
• Has there been any change in your other medication regimen(s) or medical condition(s)?
• Did you change pharmacies, or did the shape or color of your pill change?
• Have you experienced significant weight changes?
• Do you have any gastrointestinal complaints (nausea/vomiting/diarrhea/bloating)?

MEDICATION ADHERENCE
It is well known but still puzzling to hear that, overall, patients’ medication adherence is merely 50%.² It is very important that you verify whether your patient is taking his/her medication consistently. Rather than asking “Are you taking your medications?” (to which they are more likely to answer “yes”), I ask “How many pills do you miss in a given week or month?”

For those who have a hard time remembering to take their medication on a regular basis, I recommend setting up a routine: Keep the medication at their bedside and take it first thing upon awakening, or place it beside the toothpaste so they see it every time they brush their teeth in the morning. Another option is of course to set up an alarm as a reminder.

Continue for rules for taking hypothyroid >>

RULES FOR TAKING HYPOTHYROID MEDICATIONS
Thyroid hormone replacement has a narrow therapeutic index, and a subtle change in dosage can significantly alter the therapeutic target. Hypothyroid medications are absorbed in the jejunum/ileum, and an acidic pH in the stomach is optimal for thyroid absorption.³ Therefore, taking the medication on an empty stomach (fasting) with a full glass of water and waiting at least one hour before breakfast is recommended, if possible. An alternate option is to take it at bedtime, at least three hours after the last meal. Taking medication along with food, especially high-fiber and soy products, can decrease absorption of thyroid hormone, which may result in an unstable thyroid function test.

There are supplements and medications that can decrease hypothyroid medication absorption; it is recommended that patients separate these medications by four hours or more in order to minimize this interference. A full list is available in Table 2, but the most commonly encountered are iron supplements, calcium supplements, and proton pump inhibitors.²

In many patients—especially the elderly and those with multiple comorbidities that require polypharmacy—it can be very challenging, if not impossible, to isolate thyroid medication. For these patients, recommend that they be “consistent” with their routine to ensure they achieve a similar absorption rate each time. For example, a patient’s hypothyroid medication absorption might be reduced by 50% by taking it with omeprazole, but as long as the patient consistently takes the medication that way, she can have stable thyroid function.

NEW MEDICATION REGIMEN OR MEDICAL CONDITION
In addition to medications that can interfere with the absorption of thyroid hormone replacement, there are those that affect levels of thyroxine-binding globulin. This affects the bioavailability of thyroid hormones and alters thyroid status.

Thyroid hormones such as thyroxine (T4) and triiodothyronine (T3) are predominantly bound to carrier proteins, and < 1% is unbound (so-called free hormones). Changes in thyroid-binding proteins can alter free hormone levels and thereby change TSH levels. In disease-free euthyroid subjects, the body can compensate by adjusting hormone production for changes in binding proteins to keep the free hormone levels within normal ranges. However, patients who are at or near full replacement doses of hypothyroid medication cannot adjust to the changes.

In patients with hypothyroidism who are taking thyroid hormone replacement, medications or conditions that increase binding proteins will decrease free hormones (by increasing bound hormones) and thereby raise TSH (hypothyroid state). Vice versa, medications and conditions that decrease binding protein will increase free hormones (by decreasing bound hormones) and thereby lower TSH (thyrotoxic state). Table 3 lists commonly encountered medications and conditions associated with altered thyroid-binding proteins.¹

It is important to consider pregnancy in women of childbearing age whose TSH has risen for no apparent reason, as their thyroid levels should be maintained in a narrow therapeutic range to prevent fetal complications. Details on thyroid disease during pregnancy can be found in the April 2015 Endocrine Consult, “Managing Thyroid Disease in Pregnancy.”

In women treated for hypothyroidism, starting or discontinuing estrogen-containing medications (birth control pills or hormone replacement therapy) often results in changes in thyroid status. It is a good practice to inform the patient about these changes and to recheck her thyroid labs four to eight weeks after she starts or discontinues estrogen, adjusting the dose if needed.

Continue for changes in manufacturer/brand >>

CHANGES IN MANUFACTURER/BRAND
There are currently multiple brands and generic manufacturers supplying hypothyroid medications and reports that absorption rates and bioavailability vary among them.² Switching products can result in changes in thyroid status and in TSH levels.

Once a patient has reached euthyroid status, it is imperative to stay on the same dose from the same manufacturer. This may be challenging, as it can be affected by the patient’s insurance carrier, policy changes, or even a change in the pharmacy’s medication supplier. Although patients are supposed to be informed by the pharmacy when the manufacturer is being changed, you may want to educate them to check the shape, color, and dose of their pills and also verify that the manufacturer listed on the bottle is consistent each time they refill their hypothyroid medications. This is especially important for those who require a very narrow TSH target, such as young children, thyroid cancer patients, pregnant women, and frail patients.³

WEIGHT CHANGES
As mentioned, thyroid medications are weight-based, and big changes in weight can lead to changes in thyroid function studies. It is the lean body mass, rather than total body weight, that will affect the thyroid requirement.³ A quick review of the patient’s weight history needs to be done when thyroid function test results have changed.

GASTROINTESTINAL DISTURBANCES
Hypothyroid medications are absorbed in the small intestine, and gastric acidity levels have an impact on absorption. Any acute or chronic conditions that affect these areas can alter medication absorption quite significantly. Commonly encountered diseases and conditions are H pylori–related gastritis, atrophic gastritis, celiac disease, and lactose intolerance. Treating these diseases and conditions can improve medication absorption.

I went through the list with the patient, but there was no applicable scenario. I adjusted his medication but went ahead and tested for tissue transglutaminase antibody IgA to rule out celiac disease; results came back mildly positive. The patient was referred to a gastroenterologist, who performed a small intestine biopsy for definitive diagnosis. This revealed “severe” celiac disease. A strict gluten-free diet was started, and the patient’s LT4 dose was adjusted, with regular monitoring, down to 150 μg/d.

Common symptoms of celiac disease include bloating, abdominal pain, and loose stool after consumption of gluten-containing meals. It should be noted that this patient denied all these symptoms, even though he was asked specifically about them. After he started a gluten-free diet, he reported that he actually felt “very calm” in his abdomen and realized he did have symptoms of celiac disease—but he’d had them for so long that he considered it normal. As is often the case, presence of symptoms would raise suspicion ... but lack of symptoms (or report thereof) does not rule out the disease.

CONCLUSION
Most patients with hypothyroidism are fairly well managed with relatively stable medication dosages, but there are subsets of patients who struggle to maintain euthyroid range. The latter require frequent office visits and dosage changes. Carefully reviewing the list of possible reasons for thyroid level changes can improve stability and patient quality of life, prevent complications of fluctuating thyroid levels, and reduce medical costs, such as repeated labs and frequent clinic visits.

REFERENCES
1.  Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults [published correction appears in Endocr Pract. 2013;19(1):175]. Endocr Pract. 2012;18(6):988-1028.
2. Sabate E. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
3. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism. Thyroid. 2014;24(12):1670-1751.

A 43-year-old man presents for his thyroid checkup. He has known hypothyroidism secondary to Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis. He is taking levothyroxine (LT4) 250 μg (two 125-μg tablets once per day). Review of his prior lab results and notes (see Table 1) reveals frequent dose changes (about every three to six months) and a high dosage of LT4, considering his weight (185 lb).

Patients with little or no residual thyroid function require replacement doses of LT4 at approximately 1.6 μg/kg/d, based on lean body weight.¹ Since the case patient weighs 84 kg, the expected LT4 dosage would be around 125 to 150 μg/d.

This patient requires a significantly higher dose than expected, and his thyroid levels are fluctuating. These facts should trigger further investigation.

Important historical questions I consider when patients have frequent or significant fluctuations in TSH include
• Are you consistent in taking your medication?
• How do you take your thyroid medication?
• Are you taking any iron supplements, vitamins with iron, or contraceptive pills containing iron?
• Has there been any change in your other medication regimen(s) or medical condition(s)?
• Did you change pharmacies, or did the shape or color of your pill change?
• Have you experienced significant weight changes?
• Do you have any gastrointestinal complaints (nausea/vomiting/diarrhea/bloating)?

MEDICATION ADHERENCE
It is well known but still puzzling to hear that, overall, patients’ medication adherence is merely 50%.² It is very important that you verify whether your patient is taking his/her medication consistently. Rather than asking “Are you taking your medications?” (to which they are more likely to answer “yes”), I ask “How many pills do you miss in a given week or month?”

For those who have a hard time remembering to take their medication on a regular basis, I recommend setting up a routine: Keep the medication at their bedside and take it first thing upon awakening, or place it beside the toothpaste so they see it every time they brush their teeth in the morning. Another option is of course to set up an alarm as a reminder.

Continue for rules for taking hypothyroid >>

RULES FOR TAKING HYPOTHYROID MEDICATIONS
Thyroid hormone replacement has a narrow therapeutic index, and a subtle change in dosage can significantly alter the therapeutic target. Hypothyroid medications are absorbed in the jejunum/ileum, and an acidic pH in the stomach is optimal for thyroid absorption.³ Therefore, taking the medication on an empty stomach (fasting) with a full glass of water and waiting at least one hour before breakfast is recommended, if possible. An alternate option is to take it at bedtime, at least three hours after the last meal. Taking medication along with food, especially high-fiber and soy products, can decrease absorption of thyroid hormone, which may result in an unstable thyroid function test.

There are supplements and medications that can decrease hypothyroid medication absorption; it is recommended that patients separate these medications by four hours or more in order to minimize this interference. A full list is available in Table 2, but the most commonly encountered are iron supplements, calcium supplements, and proton pump inhibitors.²

In many patients—especially the elderly and those with multiple comorbidities that require polypharmacy—it can be very challenging, if not impossible, to isolate thyroid medication. For these patients, recommend that they be “consistent” with their routine to ensure they achieve a similar absorption rate each time. For example, a patient’s hypothyroid medication absorption might be reduced by 50% by taking it with omeprazole, but as long as the patient consistently takes the medication that way, she can have stable thyroid function.

NEW MEDICATION REGIMEN OR MEDICAL CONDITION
In addition to medications that can interfere with the absorption of thyroid hormone replacement, there are those that affect levels of thyroxine-binding globulin. This affects the bioavailability of thyroid hormones and alters thyroid status.

Thyroid hormones such as thyroxine (T4) and triiodothyronine (T3) are predominantly bound to carrier proteins, and < 1% is unbound (so-called free hormones). Changes in thyroid-binding proteins can alter free hormone levels and thereby change TSH levels. In disease-free euthyroid subjects, the body can compensate by adjusting hormone production for changes in binding proteins to keep the free hormone levels within normal ranges. However, patients who are at or near full replacement doses of hypothyroid medication cannot adjust to the changes.

In patients with hypothyroidism who are taking thyroid hormone replacement, medications or conditions that increase binding proteins will decrease free hormones (by increasing bound hormones) and thereby raise TSH (hypothyroid state). Vice versa, medications and conditions that decrease binding protein will increase free hormones (by decreasing bound hormones) and thereby lower TSH (thyrotoxic state). Table 3 lists commonly encountered medications and conditions associated with altered thyroid-binding proteins.¹

It is important to consider pregnancy in women of childbearing age whose TSH has risen for no apparent reason, as their thyroid levels should be maintained in a narrow therapeutic range to prevent fetal complications. Details on thyroid disease during pregnancy can be found in the April 2015 Endocrine Consult, “Managing Thyroid Disease in Pregnancy.”

In women treated for hypothyroidism, starting or discontinuing estrogen-containing medications (birth control pills or hormone replacement therapy) often results in changes in thyroid status. It is a good practice to inform the patient about these changes and to recheck her thyroid labs four to eight weeks after she starts or discontinues estrogen, adjusting the dose if needed.

Continue for changes in manufacturer/brand >>

CHANGES IN MANUFACTURER/BRAND
There are currently multiple brands and generic manufacturers supplying hypothyroid medications and reports that absorption rates and bioavailability vary among them.² Switching products can result in changes in thyroid status and in TSH levels.

Once a patient has reached euthyroid status, it is imperative to stay on the same dose from the same manufacturer. This may be challenging, as it can be affected by the patient’s insurance carrier, policy changes, or even a change in the pharmacy’s medication supplier. Although patients are supposed to be informed by the pharmacy when the manufacturer is being changed, you may want to educate them to check the shape, color, and dose of their pills and also verify that the manufacturer listed on the bottle is consistent each time they refill their hypothyroid medications. This is especially important for those who require a very narrow TSH target, such as young children, thyroid cancer patients, pregnant women, and frail patients.³

WEIGHT CHANGES
As mentioned, thyroid medications are weight-based, and big changes in weight can lead to changes in thyroid function studies. It is the lean body mass, rather than total body weight, that will affect the thyroid requirement.³ A quick review of the patient’s weight history needs to be done when thyroid function test results have changed.

GASTROINTESTINAL DISTURBANCES
Hypothyroid medications are absorbed in the small intestine, and gastric acidity levels have an impact on absorption. Any acute or chronic conditions that affect these areas can alter medication absorption quite significantly. Commonly encountered diseases and conditions are H pylori–related gastritis, atrophic gastritis, celiac disease, and lactose intolerance. Treating these diseases and conditions can improve medication absorption.

I went through the list with the patient, but there was no applicable scenario. I adjusted his medication but went ahead and tested for tissue transglutaminase antibody IgA to rule out celiac disease; results came back mildly positive. The patient was referred to a gastroenterologist, who performed a small intestine biopsy for definitive diagnosis. This revealed “severe” celiac disease. A strict gluten-free diet was started, and the patient’s LT4 dose was adjusted, with regular monitoring, down to 150 μg/d.

Common symptoms of celiac disease include bloating, abdominal pain, and loose stool after consumption of gluten-containing meals. It should be noted that this patient denied all these symptoms, even though he was asked specifically about them. After he started a gluten-free diet, he reported that he actually felt “very calm” in his abdomen and realized he did have symptoms of celiac disease—but he’d had them for so long that he considered it normal. As is often the case, presence of symptoms would raise suspicion ... but lack of symptoms (or report thereof) does not rule out the disease.

CONCLUSION
Most patients with hypothyroidism are fairly well managed with relatively stable medication dosages, but there are subsets of patients who struggle to maintain euthyroid range. The latter require frequent office visits and dosage changes. Carefully reviewing the list of possible reasons for thyroid level changes can improve stability and patient quality of life, prevent complications of fluctuating thyroid levels, and reduce medical costs, such as repeated labs and frequent clinic visits.

REFERENCES
1.  Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults [published correction appears in Endocr Pract. 2013;19(1):175]. Endocr Pract. 2012;18(6):988-1028.
2. Sabate E. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
3. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism. Thyroid. 2014;24(12):1670-1751.

A 43-year-old man presents for his thyroid checkup. He has known hypothyroidism secondary to Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis. He is taking levothyroxine (LT4) 250 μg (two 125-μg tablets once per day). Review of his prior lab results and notes (see Table 1) reveals frequent dose changes (about every three to six months) and a high dosage of LT4, considering his weight (185 lb).

Patients with little or no residual thyroid function require replacement doses of LT4 at approximately 1.6 μg/kg/d, based on lean body weight.¹ Since the case patient weighs 84 kg, the expected LT4 dosage would be around 125 to 150 μg/d.

This patient requires a significantly higher dose than expected, and his thyroid levels are fluctuating. These facts should trigger further investigation.

Important historical questions I consider when patients have frequent or significant fluctuations in TSH include
• Are you consistent in taking your medication?
• How do you take your thyroid medication?
• Are you taking any iron supplements, vitamins with iron, or contraceptive pills containing iron?
• Has there been any change in your other medication regimen(s) or medical condition(s)?
• Did you change pharmacies, or did the shape or color of your pill change?
• Have you experienced significant weight changes?
• Do you have any gastrointestinal complaints (nausea/vomiting/diarrhea/bloating)?

MEDICATION ADHERENCE
It is well known but still puzzling to hear that, overall, patients’ medication adherence is merely 50%.² It is very important that you verify whether your patient is taking his/her medication consistently. Rather than asking “Are you taking your medications?” (to which they are more likely to answer “yes”), I ask “How many pills do you miss in a given week or month?”

For those who have a hard time remembering to take their medication on a regular basis, I recommend setting up a routine: Keep the medication at their bedside and take it first thing upon awakening, or place it beside the toothpaste so they see it every time they brush their teeth in the morning. Another option is of course to set up an alarm as a reminder.

Continue for rules for taking hypothyroid >>

RULES FOR TAKING HYPOTHYROID MEDICATIONS
Thyroid hormone replacement has a narrow therapeutic index, and a subtle change in dosage can significantly alter the therapeutic target. Hypothyroid medications are absorbed in the jejunum/ileum, and an acidic pH in the stomach is optimal for thyroid absorption.³ Therefore, taking the medication on an empty stomach (fasting) with a full glass of water and waiting at least one hour before breakfast is recommended, if possible. An alternate option is to take it at bedtime, at least three hours after the last meal. Taking medication along with food, especially high-fiber and soy products, can decrease absorption of thyroid hormone, which may result in an unstable thyroid function test.

There are supplements and medications that can decrease hypothyroid medication absorption; it is recommended that patients separate these medications by four hours or more in order to minimize this interference. A full list is available in Table 2, but the most commonly encountered are iron supplements, calcium supplements, and proton pump inhibitors.²

In many patients—especially the elderly and those with multiple comorbidities that require polypharmacy—it can be very challenging, if not impossible, to isolate thyroid medication. For these patients, recommend that they be “consistent” with their routine to ensure they achieve a similar absorption rate each time. For example, a patient’s hypothyroid medication absorption might be reduced by 50% by taking it with omeprazole, but as long as the patient consistently takes the medication that way, she can have stable thyroid function.

NEW MEDICATION REGIMEN OR MEDICAL CONDITION
In addition to medications that can interfere with the absorption of thyroid hormone replacement, there are those that affect levels of thyroxine-binding globulin. This affects the bioavailability of thyroid hormones and alters thyroid status.

Thyroid hormones such as thyroxine (T4) and triiodothyronine (T3) are predominantly bound to carrier proteins, and < 1% is unbound (so-called free hormones). Changes in thyroid-binding proteins can alter free hormone levels and thereby change TSH levels. In disease-free euthyroid subjects, the body can compensate by adjusting hormone production for changes in binding proteins to keep the free hormone levels within normal ranges. However, patients who are at or near full replacement doses of hypothyroid medication cannot adjust to the changes.

In patients with hypothyroidism who are taking thyroid hormone replacement, medications or conditions that increase binding proteins will decrease free hormones (by increasing bound hormones) and thereby raise TSH (hypothyroid state). Vice versa, medications and conditions that decrease binding protein will increase free hormones (by decreasing bound hormones) and thereby lower TSH (thyrotoxic state). Table 3 lists commonly encountered medications and conditions associated with altered thyroid-binding proteins.¹

It is important to consider pregnancy in women of childbearing age whose TSH has risen for no apparent reason, as their thyroid levels should be maintained in a narrow therapeutic range to prevent fetal complications. Details on thyroid disease during pregnancy can be found in the April 2015 Endocrine Consult, “Managing Thyroid Disease in Pregnancy.”

In women treated for hypothyroidism, starting or discontinuing estrogen-containing medications (birth control pills or hormone replacement therapy) often results in changes in thyroid status. It is a good practice to inform the patient about these changes and to recheck her thyroid labs four to eight weeks after she starts or discontinues estrogen, adjusting the dose if needed.

Continue for changes in manufacturer/brand >>

CHANGES IN MANUFACTURER/BRAND
There are currently multiple brands and generic manufacturers supplying hypothyroid medications and reports that absorption rates and bioavailability vary among them.² Switching products can result in changes in thyroid status and in TSH levels.

Once a patient has reached euthyroid status, it is imperative to stay on the same dose from the same manufacturer. This may be challenging, as it can be affected by the patient’s insurance carrier, policy changes, or even a change in the pharmacy’s medication supplier. Although patients are supposed to be informed by the pharmacy when the manufacturer is being changed, you may want to educate them to check the shape, color, and dose of their pills and also verify that the manufacturer listed on the bottle is consistent each time they refill their hypothyroid medications. This is especially important for those who require a very narrow TSH target, such as young children, thyroid cancer patients, pregnant women, and frail patients.³

WEIGHT CHANGES
As mentioned, thyroid medications are weight-based, and big changes in weight can lead to changes in thyroid function studies. It is the lean body mass, rather than total body weight, that will affect the thyroid requirement.³ A quick review of the patient’s weight history needs to be done when thyroid function test results have changed.

GASTROINTESTINAL DISTURBANCES
Hypothyroid medications are absorbed in the small intestine, and gastric acidity levels have an impact on absorption. Any acute or chronic conditions that affect these areas can alter medication absorption quite significantly. Commonly encountered diseases and conditions are H pylori–related gastritis, atrophic gastritis, celiac disease, and lactose intolerance. Treating these diseases and conditions can improve medication absorption.

I went through the list with the patient, but there was no applicable scenario. I adjusted his medication but went ahead and tested for tissue transglutaminase antibody IgA to rule out celiac disease; results came back mildly positive. The patient was referred to a gastroenterologist, who performed a small intestine biopsy for definitive diagnosis. This revealed “severe” celiac disease. A strict gluten-free diet was started, and the patient’s LT4 dose was adjusted, with regular monitoring, down to 150 μg/d.

Common symptoms of celiac disease include bloating, abdominal pain, and loose stool after consumption of gluten-containing meals. It should be noted that this patient denied all these symptoms, even though he was asked specifically about them. After he started a gluten-free diet, he reported that he actually felt “very calm” in his abdomen and realized he did have symptoms of celiac disease—but he’d had them for so long that he considered it normal. As is often the case, presence of symptoms would raise suspicion ... but lack of symptoms (or report thereof) does not rule out the disease.

CONCLUSION
Most patients with hypothyroidism are fairly well managed with relatively stable medication dosages, but there are subsets of patients who struggle to maintain euthyroid range. The latter require frequent office visits and dosage changes. Carefully reviewing the list of possible reasons for thyroid level changes can improve stability and patient quality of life, prevent complications of fluctuating thyroid levels, and reduce medical costs, such as repeated labs and frequent clinic visits.

REFERENCES
1.  Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults [published correction appears in Endocr Pract. 2013;19(1):175]. Endocr Pract. 2012;18(6):988-1028.
2. Sabate E. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.
3. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism. Thyroid. 2014;24(12):1670-1751.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; nahmed-sarwar@sjfc.edu

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; nahmed-sarwar@sjfc.edu

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; nahmed-sarwar@sjfc.edu

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

A 54-year-old woman with chronic renal disease was diagnosed with gout and prescribed allopurinol. Two days later, she was evaluated by her nephrologist, whom she informed about her new medication.

Subsequently, the patient developed fever and rash. Laboratory analysis indicated elevated transaminase levels and eosinophilia. She was admitted to the hospital.

During her stay, an infectious disease consultation was obtained, and the allopurinol was discontinued. When the patient’s condition improved, she was discharged.

Following discharge, the patient resumed taking allopurinol, and her rash returned. Eleven days later, she returned to the hospital, where she was diagnosed with toxic epidermal necrolysis. She was found to have a desquamating rash covering 62% of her body. The patient was transferred to a burn center but eventually succumbed to multi-organ failure.

The patient’s estate filed a medical malpractice lawsuit against the nephrologist alleging negligence—specifically, failure to diagnose toxic epidermal necrolysis and failure to review her medications more carefully.

Continue for the outcome >>

OUTCOME
A $5.1 million verdict was returned against the nephrologist.

COMMENT
Many medications cause rash and are subsequently withdrawn; in a few cases, the effects are life threatening. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are relatively uncommon but potentially fatal examples.

From the limited facts presented, we know that a 54-year-old woman with established renal disease of unknown magnitude was prescribed allopurinol for gout and consulted the nephrologist two days later. It is unclear if the patient had the rash during the first visit with her nephrologist. But we do know that she was eventually admitted and maintained on allopurinol while she had the rash, pending infectious disease consultation. At some point, the allopurinol was apparently stopped and the rash improved. After discharge, the patient resumed taking allopurinol. The rash not only returned but also worsened, necessitating her readmission to a burn center.

TEN, like SJS, is often induced by certain medications, including sulfonamides, macrolides, penicillins, and quinolones. Allopur­inol, phenobarbital, phenytoin, carbamazepine, valproic acid, and lamotrigine are frequently implicated as well.

TEN is rare but serious. The initial presentation may be subtle, with influenza-like symptoms such as malaise, fever, cough, rhinitis, headache, and arthralgia—and the most discriminating sign: rash.

The rash begins as a poorly defined, erythematous macular rash with purpuric centers. The lesions predominate on the torso and face, sparing the scalp. Mucosal membranes are involved in more than 90% of cases.¹ Pain at the site of the skin lesions is often the predominate symptom and is often out of proportion to physical findings. Over a period of hours to days, the rash coalesces to form flaccid blisters and sheetlike epidermal detachment.² In established cases, patients will nearly universally demonstrate Nikolsky’s sign: Mild frictional contact with the skin results in epithelial desquamation and immediate blistering.

Management involves immediate withdrawal of the offending agent and hospitalization for aggressive management. The mortality rate is high (30% to 60%³) and generally attributed to sepsis or multi-organ failure.

As clinicians, we are sometimes hesitant to label a rash allergic—thereby forever disqualifying an entire class of useful agents from that patient. However, in this case, the fact that the rash occurred simultaneously with a constellation of signs and symptoms perhaps made the rash appear to be part of an infectious process and not a drug-induced reaction. That is the challenge with TEN and SJS: The symptoms are subtle, flu-like, and confounding.

Here, the nephrologist apparently did not take action to stop the allopurinol after the patient first developed the rash. The jury was persuaded that a reasonably prudent clinician would have recognized the clinical presentation and stopped the allopurinol—and certainly not restarted it following discharge (especially after the allopurinol was stopped in the hospital and the rash began to improve).

This case brings to mind two physicians from my training who made an impression. The first was a second-year internal medicine resident. I remember quietly remarking to another student during rounds, “He is really good.” Overhearing, an attending physician answered, “He is really good because in his workup he always considers a presentation as a function of an underlying process, and walks through each of those processes in formulating his differential.”

“Walking through” various disease categories forces the clinician to consider them all: infectious, autoimmune, neoplastic, environmental/toxic, vascular, traumatic, metabolic, inflammatory. In challenging cases, I’ve found it helpful to step backward into those broad basic categories of disease and reconsider the clinical picture.

Here, doing so may have allowed the clinician to reconsider inflammatory and autoimmune processes and revisit the possibility of iatrogenic toxic/environmental causes (ie, the allopurinol). Perhaps the outcome of this case would have been different.

The second physician was a nephrology fellow, who left me with this piece of wisdom: “When in doubt, blame the drug.” Since nephrologists are expert drug-blamers, I suspect the early stages of this unfortunate case presented a clinical challenge.

IN SUM 
Before you “missile lock” onto a diagnosis, take a mental step back to consider broad categories of disease. —DML

REFERENCES
1. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4):419-436.
2. Cohen V, Jellinek SP, Schwartz RA, et al. Toxic epidermal necrolysis.  Medscape; 2013. emedicine.medscape.com/article/229698-overview. Accessed September 16, 2015.
3. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3): 199-204.

LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.

Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.

Clever Cupcakes/Flickr/CC BY-SA 2.0/No changes

Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.

Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.

This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.

Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”

If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.

Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.

Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.

Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:

• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.

• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.

• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.

• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.

• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.

• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.

• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.

Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.

Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.

Clever Cupcakes/Flickr/CC BY-SA 2.0/No changes

Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.

Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.

This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.

Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”

If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.

Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.

Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.

Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:

• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.

• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.

• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.

• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.

• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.

• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.

• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.

Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.

Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.

Clever Cupcakes/Flickr/CC BY-SA 2.0/No changes

Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.

Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.

This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.

Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”

If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.

Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.

Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.

Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:

• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.

• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.

• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.

• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.

• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.

• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.

• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.

Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.

koakes@frontlinemedcom.com

On Twitter @karioakes

Hereditary syndromes in gastroenterology have emerged from being esoteric to being common issues that all of us must deal with, according to Dr. Sapna Syngal of Dana-Farber/Brigham and Women’s Cancer Center, Boston. Screening, surveillance, and treatment of hereditary cancers are all different, compared with sporadic cancer. For colorectal cancers, an excellent resource is http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf, and there are recent society summaries (Am. J. Gastroenterol. 2015;110:223-62). These recommend a family history of cancer be recorded for all patients, including type of cancer, age at diagnosis, and relationship to patient. Lynch syndrome testing should now be done on all newly diagnosed colorectal cancers by testing of mismatch repair proteins or microsatellite instability. Genetic testing should be done when these are detected and on all family members of affected individuals. Familial adenomatous polyposis testing, including the APC and MUTYH genes, should be done for individuals with more than 10 cumulative adenomas, or a family history of any familial adenomatous condition. Peutz-Jeghers syndrome should be tested for in individuals with perioral/buccal pigmentation or those with two or more hamartomatous polyps. Juvenile polyposis syndrome should be tested for in individuals with five or more juvenile polyps in the colorectum or any juvenile polyps in other parts of the GI tract. Simple clinical questions can help identify those who should be tested (Am. J. Gastroenterol. 2009;104:1508-18).

Modern evidence has refuted several long-held beliefs about diverticulosis and diverticulitis, said Dr. Neil Stollman of the University of California, San Francisco. Evidence now shows that diverticulosis is not associated with a low-fiber diet and that high-fiber diets are associated with higher rates of diverticular complications, although this may be due to confounding. Nonsteroidal anti-inflammatory drugs are associated with increased risk of diverticular bleeding. The risk of diverticulitis is much lower than previously thought. Prior estimates of 10%-25% have now been revised downward to 1%-4%. Nuts and seeds do not cause acute diverticulitis and do not need to be avoided. Diverticulitis is a spectrum of diseases from asymptomatic to symptomatic uncomplicated diverticular disease (SUDD) to acute diverticulitis. Mesalamine may be effective in SUDD and acute diverticulitis but evidence is mixed. Cyclic rifaximin and probiotics may also be helpful in SUDD. Antibiotics, previously thought to be mandatory in acute diverticulitis, have not been clearly beneficial in large randomized trials. Surgery, which was also previously recommended after a second attack of acute diverticulitis, is now considered optional and should be individualized.

Dr. Douglas K. Rex of Indiana University Health, Indianapolis, reviewed key measures of quality in colonoscopy and how to achieve these, even under difficult circumstances. Key measures include adenoma detection rate, which can be improved through careful attention to good technique (looking behind folds, adequate distention, and washing) and recognition of flat and sessile polyps. New technologies include high definition, special endoscope caps that flatten folds, and new wide-angle colonoscopes. Water immersion and CO₂ insufflation have also improved quality through easier insertion and less gas distention and pain after the procedure. For removal of large, lateral spreading polyps, the technique of endoscopic mucosal resection has been highly effective. Use of a “bulking agent” for submucosal injection such as hydroxyethyl starch, injectable contrast agent, underwater endoscopic mucosal resection, and avulsion (with cold or hot forceps) of fibrotic/scarred polyps have all been demonstrated to be effective in expert hands.

Dr. Charlene M. Prather of Saint Louis University summarized the increasing prevalence of constipation and reviewed risk factors (decreased activity, low fiber consumption, and use of multiple constipating medications). Constipation can be divided into three types: normal transit, slow transit, and pelvic floor dysfunction (PFD). Physical exam, particularly a high-quality rectal exam, can be very effective with high negative predictive value for PFD. Treatment includes fiber supplementation (most effective for mild/moderate constipation, less helpful in slow transit or PFD), laxatives (best data are for osmotic laxatives and bisacodyl), and newer agents that stimulate chloride secretion. Testing is appropriate for refractory constipation and includes transit time studies, balloon expulsion, and anorectal manometry.

Dr. Brennan Spiegel of the Cedars-Sinai Center for Outcomes Research and Education, Los Angeles, provided a summary of current national efforts to measure, report, and improve quality in gastroenterology. He highlighted several reports of high variability in quality such as adenoma detection, testing in patients with uncomplicated inflammatory bowel disease, and approaches to diagnosis of irritable bowel syndrome. A general approach to achieving quality was outlined, including: 1. standardization, 2. measurement, 3. reporting, 4. incentivizing (getting paid for performance), and 5. improving. U.S. Medicare oversight groups (PQRS) have chosen four general areas of quality (polyp surveillance, gastroesophageal reflux disease, hepatitis C, and IBD) measures. Gastroenterology societies have provided effective tools to measure and report these, including GIQUIC and the AGA Digestive Health Recognition Program.

Dr. Wallace is professor of medicine and director, digestive diseases research program, Mayo Clinic, Jacksonville, Fla. He has received grants from BSCI and Cosmo and has consulted for Olympus and iLumen. This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2015.

Hereditary syndromes in gastroenterology have emerged from being esoteric to being common issues that all of us must deal with, according to Dr. Sapna Syngal of Dana-Farber/Brigham and Women’s Cancer Center, Boston. Screening, surveillance, and treatment of hereditary cancers are all different, compared with sporadic cancer. For colorectal cancers, an excellent resource is http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf, and there are recent society summaries (Am. J. Gastroenterol. 2015;110:223-62). These recommend a family history of cancer be recorded for all patients, including type of cancer, age at diagnosis, and relationship to patient. Lynch syndrome testing should now be done on all newly diagnosed colorectal cancers by testing of mismatch repair proteins or microsatellite instability. Genetic testing should be done when these are detected and on all family members of affected individuals. Familial adenomatous polyposis testing, including the APC and MUTYH genes, should be done for individuals with more than 10 cumulative adenomas, or a family history of any familial adenomatous condition. Peutz-Jeghers syndrome should be tested for in individuals with perioral/buccal pigmentation or those with two or more hamartomatous polyps. Juvenile polyposis syndrome should be tested for in individuals with five or more juvenile polyps in the colorectum or any juvenile polyps in other parts of the GI tract. Simple clinical questions can help identify those who should be tested (Am. J. Gastroenterol. 2009;104:1508-18).

Modern evidence has refuted several long-held beliefs about diverticulosis and diverticulitis, said Dr. Neil Stollman of the University of California, San Francisco. Evidence now shows that diverticulosis is not associated with a low-fiber diet and that high-fiber diets are associated with higher rates of diverticular complications, although this may be due to confounding. Nonsteroidal anti-inflammatory drugs are associated with increased risk of diverticular bleeding. The risk of diverticulitis is much lower than previously thought. Prior estimates of 10%-25% have now been revised downward to 1%-4%. Nuts and seeds do not cause acute diverticulitis and do not need to be avoided. Diverticulitis is a spectrum of diseases from asymptomatic to symptomatic uncomplicated diverticular disease (SUDD) to acute diverticulitis. Mesalamine may be effective in SUDD and acute diverticulitis but evidence is mixed. Cyclic rifaximin and probiotics may also be helpful in SUDD. Antibiotics, previously thought to be mandatory in acute diverticulitis, have not been clearly beneficial in large randomized trials. Surgery, which was also previously recommended after a second attack of acute diverticulitis, is now considered optional and should be individualized.

Dr. Douglas K. Rex of Indiana University Health, Indianapolis, reviewed key measures of quality in colonoscopy and how to achieve these, even under difficult circumstances. Key measures include adenoma detection rate, which can be improved through careful attention to good technique (looking behind folds, adequate distention, and washing) and recognition of flat and sessile polyps. New technologies include high definition, special endoscope caps that flatten folds, and new wide-angle colonoscopes. Water immersion and CO₂ insufflation have also improved quality through easier insertion and less gas distention and pain after the procedure. For removal of large, lateral spreading polyps, the technique of endoscopic mucosal resection has been highly effective. Use of a “bulking agent” for submucosal injection such as hydroxyethyl starch, injectable contrast agent, underwater endoscopic mucosal resection, and avulsion (with cold or hot forceps) of fibrotic/scarred polyps have all been demonstrated to be effective in expert hands.

Dr. Charlene M. Prather of Saint Louis University summarized the increasing prevalence of constipation and reviewed risk factors (decreased activity, low fiber consumption, and use of multiple constipating medications). Constipation can be divided into three types: normal transit, slow transit, and pelvic floor dysfunction (PFD). Physical exam, particularly a high-quality rectal exam, can be very effective with high negative predictive value for PFD. Treatment includes fiber supplementation (most effective for mild/moderate constipation, less helpful in slow transit or PFD), laxatives (best data are for osmotic laxatives and bisacodyl), and newer agents that stimulate chloride secretion. Testing is appropriate for refractory constipation and includes transit time studies, balloon expulsion, and anorectal manometry.

Dr. Brennan Spiegel of the Cedars-Sinai Center for Outcomes Research and Education, Los Angeles, provided a summary of current national efforts to measure, report, and improve quality in gastroenterology. He highlighted several reports of high variability in quality such as adenoma detection, testing in patients with uncomplicated inflammatory bowel disease, and approaches to diagnosis of irritable bowel syndrome. A general approach to achieving quality was outlined, including: 1. standardization, 2. measurement, 3. reporting, 4. incentivizing (getting paid for performance), and 5. improving. U.S. Medicare oversight groups (PQRS) have chosen four general areas of quality (polyp surveillance, gastroesophageal reflux disease, hepatitis C, and IBD) measures. Gastroenterology societies have provided effective tools to measure and report these, including GIQUIC and the AGA Digestive Health Recognition Program.

Dr. Wallace is professor of medicine and director, digestive diseases research program, Mayo Clinic, Jacksonville, Fla. He has received grants from BSCI and Cosmo and has consulted for Olympus and iLumen. This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2015.

Hereditary syndromes in gastroenterology have emerged from being esoteric to being common issues that all of us must deal with, according to Dr. Sapna Syngal of Dana-Farber/Brigham and Women’s Cancer Center, Boston. Screening, surveillance, and treatment of hereditary cancers are all different, compared with sporadic cancer. For colorectal cancers, an excellent resource is http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf, and there are recent society summaries (Am. J. Gastroenterol. 2015;110:223-62). These recommend a family history of cancer be recorded for all patients, including type of cancer, age at diagnosis, and relationship to patient. Lynch syndrome testing should now be done on all newly diagnosed colorectal cancers by testing of mismatch repair proteins or microsatellite instability. Genetic testing should be done when these are detected and on all family members of affected individuals. Familial adenomatous polyposis testing, including the APC and MUTYH genes, should be done for individuals with more than 10 cumulative adenomas, or a family history of any familial adenomatous condition. Peutz-Jeghers syndrome should be tested for in individuals with perioral/buccal pigmentation or those with two or more hamartomatous polyps. Juvenile polyposis syndrome should be tested for in individuals with five or more juvenile polyps in the colorectum or any juvenile polyps in other parts of the GI tract. Simple clinical questions can help identify those who should be tested (Am. J. Gastroenterol. 2009;104:1508-18).

Modern evidence has refuted several long-held beliefs about diverticulosis and diverticulitis, said Dr. Neil Stollman of the University of California, San Francisco. Evidence now shows that diverticulosis is not associated with a low-fiber diet and that high-fiber diets are associated with higher rates of diverticular complications, although this may be due to confounding. Nonsteroidal anti-inflammatory drugs are associated with increased risk of diverticular bleeding. The risk of diverticulitis is much lower than previously thought. Prior estimates of 10%-25% have now been revised downward to 1%-4%. Nuts and seeds do not cause acute diverticulitis and do not need to be avoided. Diverticulitis is a spectrum of diseases from asymptomatic to symptomatic uncomplicated diverticular disease (SUDD) to acute diverticulitis. Mesalamine may be effective in SUDD and acute diverticulitis but evidence is mixed. Cyclic rifaximin and probiotics may also be helpful in SUDD. Antibiotics, previously thought to be mandatory in acute diverticulitis, have not been clearly beneficial in large randomized trials. Surgery, which was also previously recommended after a second attack of acute diverticulitis, is now considered optional and should be individualized.

Dr. Douglas K. Rex of Indiana University Health, Indianapolis, reviewed key measures of quality in colonoscopy and how to achieve these, even under difficult circumstances. Key measures include adenoma detection rate, which can be improved through careful attention to good technique (looking behind folds, adequate distention, and washing) and recognition of flat and sessile polyps. New technologies include high definition, special endoscope caps that flatten folds, and new wide-angle colonoscopes. Water immersion and CO₂ insufflation have also improved quality through easier insertion and less gas distention and pain after the procedure. For removal of large, lateral spreading polyps, the technique of endoscopic mucosal resection has been highly effective. Use of a “bulking agent” for submucosal injection such as hydroxyethyl starch, injectable contrast agent, underwater endoscopic mucosal resection, and avulsion (with cold or hot forceps) of fibrotic/scarred polyps have all been demonstrated to be effective in expert hands.

Dr. Charlene M. Prather of Saint Louis University summarized the increasing prevalence of constipation and reviewed risk factors (decreased activity, low fiber consumption, and use of multiple constipating medications). Constipation can be divided into three types: normal transit, slow transit, and pelvic floor dysfunction (PFD). Physical exam, particularly a high-quality rectal exam, can be very effective with high negative predictive value for PFD. Treatment includes fiber supplementation (most effective for mild/moderate constipation, less helpful in slow transit or PFD), laxatives (best data are for osmotic laxatives and bisacodyl), and newer agents that stimulate chloride secretion. Testing is appropriate for refractory constipation and includes transit time studies, balloon expulsion, and anorectal manometry.

Dr. Brennan Spiegel of the Cedars-Sinai Center for Outcomes Research and Education, Los Angeles, provided a summary of current national efforts to measure, report, and improve quality in gastroenterology. He highlighted several reports of high variability in quality such as adenoma detection, testing in patients with uncomplicated inflammatory bowel disease, and approaches to diagnosis of irritable bowel syndrome. A general approach to achieving quality was outlined, including: 1. standardization, 2. measurement, 3. reporting, 4. incentivizing (getting paid for performance), and 5. improving. U.S. Medicare oversight groups (PQRS) have chosen four general areas of quality (polyp surveillance, gastroesophageal reflux disease, hepatitis C, and IBD) measures. Gastroenterology societies have provided effective tools to measure and report these, including GIQUIC and the AGA Digestive Health Recognition Program.

Dr. Wallace is professor of medicine and director, digestive diseases research program, Mayo Clinic, Jacksonville, Fla. He has received grants from BSCI and Cosmo and has consulted for Olympus and iLumen. This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2015.