The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

jevans@frontlinemedcom.com

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

jevans@frontlinemedcom.com

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

jevans@frontlinemedcom.com

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

agallegos@frontlinemedcom.com

On Twitter @legal_med

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

agallegos@frontlinemedcom.com

On Twitter @legal_med

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

agallegos@frontlinemedcom.com

On Twitter @legal_med

Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.

Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.

Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.

Endometriosis is associated with a significantly increased risk of coronary heart disease, at least in part because of one of its principal treatments – hysterectomy/oophorectomy, according to a new analysis of the Nurses’ Health Study II.

In what the researchers described as the first large prospective study to examine this possible association, the link between endometriosis and coronary heart disease (CHD) was mediated by patient age.

©designer491/Thinkstock

Women with endometriosis had a higher incidence of CHD than those without the gynecologic disorder until they reached their late 50s; after that, the two populations had similar CHD rates, wrote Fan Mu, Sc.D., of the department of epidemiology, Harvard T. H. Chan School of Public Health in Boston, and her associates (Circ Cardiovasc Qual Outcomes. 2016 Mar 29. doi: 10.1161/circoutcomes.115.002224).

“This association may have important clinical and public health implications among women in their early 40s to early 50s,” the researchers wrote. “It is possible that the observed increased risk associated with surgical menopause from hysterectomy/oophorectomy among women with endometriosis started to diminish with age partially because nearly every woman had reached menopause by the age of 55 years.”

The researchers chose to study this topic because endometriosis has been linked to chronic systemic inflammation, oxidative stress, and adverse lipid profiles, factors that also play key roles in the pathogenesis of atherosclerotic CHD. They assessed the incidence of myocardial infarction, angina, and the combined outcome of coronary artery bypass graft (CABG)/angioplasty/stenting using data from the Nurses’ Health Study II, a prospective cohort study involving 116,430 women, aged 25-42 years at baseline in 1989, who were followed for approximately 20 years.

A total of 5,296 of the study participants had laparoscopically confirmed endometriosis at baseline, and another 6,607 developed the disorder during follow-up. There were 1,438 incident cases of CHD during follow-up.

Compared with women who didn’t have endometriosis, those who did showed increased relative risks for myocardial infarction (1.63), angiographically confirmed angina (2.07), CABG/angioplasty/stent (1.49), and combined CHD (1.73). The results remained statistically significant after the researchers adjusted for potential confounders.

About 42% of this association was statistically accounted for by the greater frequency of hysterectomy/oophorectomy among women who had endometriosis and the earlier age of these surgeries among women with endometriosis. Women who underwent the surgery had an absolute incidence of CHD of 139 per 100,000 person-years, compared with an incidence of 60 per 100,000 person-years among the women who didn’t have hysterectomy/oophorectomy.

“Physicians need to consider the potential long-term impact that the surgeries may cause and weigh the risks and benefits of the treatment in dialogue with patients, particularly with respect to endometriosis where pain recurrence risk remains,” the researchers wrote. “Although oophorectomy confers obvious prevention for ovarian cancer, with which endometriosis has been associated, CHD is the leading cause of mortality and morbidity in women in the United States and United Kingdom.”

The study was supported by the National Institutes of Health. The researchers reported having no relevant financial disclosures.

Endometriosis is associated with a significantly increased risk of coronary heart disease, at least in part because of one of its principal treatments – hysterectomy/oophorectomy, according to a new analysis of the Nurses’ Health Study II.

In what the researchers described as the first large prospective study to examine this possible association, the link between endometriosis and coronary heart disease (CHD) was mediated by patient age.

©designer491/Thinkstock

Women with endometriosis had a higher incidence of CHD than those without the gynecologic disorder until they reached their late 50s; after that, the two populations had similar CHD rates, wrote Fan Mu, Sc.D., of the department of epidemiology, Harvard T. H. Chan School of Public Health in Boston, and her associates (Circ Cardiovasc Qual Outcomes. 2016 Mar 29. doi: 10.1161/circoutcomes.115.002224).

“This association may have important clinical and public health implications among women in their early 40s to early 50s,” the researchers wrote. “It is possible that the observed increased risk associated with surgical menopause from hysterectomy/oophorectomy among women with endometriosis started to diminish with age partially because nearly every woman had reached menopause by the age of 55 years.”

The researchers chose to study this topic because endometriosis has been linked to chronic systemic inflammation, oxidative stress, and adverse lipid profiles, factors that also play key roles in the pathogenesis of atherosclerotic CHD. They assessed the incidence of myocardial infarction, angina, and the combined outcome of coronary artery bypass graft (CABG)/angioplasty/stenting using data from the Nurses’ Health Study II, a prospective cohort study involving 116,430 women, aged 25-42 years at baseline in 1989, who were followed for approximately 20 years.

A total of 5,296 of the study participants had laparoscopically confirmed endometriosis at baseline, and another 6,607 developed the disorder during follow-up. There were 1,438 incident cases of CHD during follow-up.

Compared with women who didn’t have endometriosis, those who did showed increased relative risks for myocardial infarction (1.63), angiographically confirmed angina (2.07), CABG/angioplasty/stent (1.49), and combined CHD (1.73). The results remained statistically significant after the researchers adjusted for potential confounders.

About 42% of this association was statistically accounted for by the greater frequency of hysterectomy/oophorectomy among women who had endometriosis and the earlier age of these surgeries among women with endometriosis. Women who underwent the surgery had an absolute incidence of CHD of 139 per 100,000 person-years, compared with an incidence of 60 per 100,000 person-years among the women who didn’t have hysterectomy/oophorectomy.

“Physicians need to consider the potential long-term impact that the surgeries may cause and weigh the risks and benefits of the treatment in dialogue with patients, particularly with respect to endometriosis where pain recurrence risk remains,” the researchers wrote. “Although oophorectomy confers obvious prevention for ovarian cancer, with which endometriosis has been associated, CHD is the leading cause of mortality and morbidity in women in the United States and United Kingdom.”

The study was supported by the National Institutes of Health. The researchers reported having no relevant financial disclosures.

Endometriosis is associated with a significantly increased risk of coronary heart disease, at least in part because of one of its principal treatments – hysterectomy/oophorectomy, according to a new analysis of the Nurses’ Health Study II.

In what the researchers described as the first large prospective study to examine this possible association, the link between endometriosis and coronary heart disease (CHD) was mediated by patient age.

©designer491/Thinkstock

Women with endometriosis had a higher incidence of CHD than those without the gynecologic disorder until they reached their late 50s; after that, the two populations had similar CHD rates, wrote Fan Mu, Sc.D., of the department of epidemiology, Harvard T. H. Chan School of Public Health in Boston, and her associates (Circ Cardiovasc Qual Outcomes. 2016 Mar 29. doi: 10.1161/circoutcomes.115.002224).

“This association may have important clinical and public health implications among women in their early 40s to early 50s,” the researchers wrote. “It is possible that the observed increased risk associated with surgical menopause from hysterectomy/oophorectomy among women with endometriosis started to diminish with age partially because nearly every woman had reached menopause by the age of 55 years.”

The researchers chose to study this topic because endometriosis has been linked to chronic systemic inflammation, oxidative stress, and adverse lipid profiles, factors that also play key roles in the pathogenesis of atherosclerotic CHD. They assessed the incidence of myocardial infarction, angina, and the combined outcome of coronary artery bypass graft (CABG)/angioplasty/stenting using data from the Nurses’ Health Study II, a prospective cohort study involving 116,430 women, aged 25-42 years at baseline in 1989, who were followed for approximately 20 years.

A total of 5,296 of the study participants had laparoscopically confirmed endometriosis at baseline, and another 6,607 developed the disorder during follow-up. There were 1,438 incident cases of CHD during follow-up.

Compared with women who didn’t have endometriosis, those who did showed increased relative risks for myocardial infarction (1.63), angiographically confirmed angina (2.07), CABG/angioplasty/stent (1.49), and combined CHD (1.73). The results remained statistically significant after the researchers adjusted for potential confounders.

About 42% of this association was statistically accounted for by the greater frequency of hysterectomy/oophorectomy among women who had endometriosis and the earlier age of these surgeries among women with endometriosis. Women who underwent the surgery had an absolute incidence of CHD of 139 per 100,000 person-years, compared with an incidence of 60 per 100,000 person-years among the women who didn’t have hysterectomy/oophorectomy.

“Physicians need to consider the potential long-term impact that the surgeries may cause and weigh the risks and benefits of the treatment in dialogue with patients, particularly with respect to endometriosis where pain recurrence risk remains,” the researchers wrote. “Although oophorectomy confers obvious prevention for ovarian cancer, with which endometriosis has been associated, CHD is the leading cause of mortality and morbidity in women in the United States and United Kingdom.”

The study was supported by the National Institutes of Health. The researchers reported having no relevant financial disclosures.

CASE › A 66-year-old man you have seen many times for issues related to his chronic obstructive pulmonary disease (COPD) comes in to your clinic for a routine visit. He has been taking budesonide/formoterol twice a day for the last 3 years; however, he has not always been compliant with his medications and has been hospitalized within the last 6 months for disease exacerbations. Today, he says he has difficulty falling asleep and often becomes short of breath, even when physically inactive. His wife, who is accompanying him today, tells you he has become increasingly distant over the past few months and is not as engaged at family outings, which he attributes to labored breathing. They’re both concerned about this change and ask for advice.

Despite the increased awareness that generalized anxiety disorder (GAD) and major depressive disorder (MDD) are common comorbidities of COPD, they remain underdiagnosed and undertreated in patients with COPD. The results are increased rates of symptom exacerbation and rehospitalization.¹ Family physicians, who are the primary caregivers for most patients with the disease,² can maximize patients’ quality of life by recognizing comorbid mental illness, motivating and engaging patients in their disease management, and initiating appropriate treatment.

Anxiety and depression in COPD: A 2-way street

Several studies have assessed the prevalence of psychological disorders in patients with COPD. Affective disorders, mainly GAD and MDD, are the ones most commonly associated with poor COPD prognoses.^3,4 GAD is at least 3 times more prevalent in patients with COPD than in the general US population,⁵ reaching upwards of 55%.^1,6 Prevalence of MDD is also high, affecting approximately 40% of patients with the disease.¹

GAD and MDD are more prevalent as comorbidities of COPD than they are with other chronic diseases such as orthopedic conditions, pulmonary tuberculosis, hypertension and heart disease, stroke, diabetes, and cancer.^5,7-9 Patients with COPD, more so than patients with other serious chronic diseases, report heightened edginess, anxiousness, tiredness, distractibility, and irritability,⁵ perhaps owing in part to breathlessness and “air hunger.”¹⁰

The connection between COPD and GAD or MDD is not unidirectional, with progression of lung disease exacerbating its psychological comorbidities. The interaction is reciprocal, as clarified by Atlantis, et al, in a 2013 systematic review and meta-analysis that assessed key variables in the development of COPD and GAD or MDD.¹¹

COPD increases the risk of MDD, which is associated with increased tobacco consumption, poor adherence with COPD medications, and decreased physical activity.¹¹ Compounding the problem of inactivity is the fact that COPD—particularly longstanding disease—can lead to volume reductions in the anterior cingulate cortex of patients, which correlates with a persistent fear of performing physical activity.¹² MDD in the setting of COPD also complicates the already complex interplay between nicotine dependence and attempts at smoking cessation.¹¹

GAD/MDD worsens COPD outcomes

Comorbid GAD and MDD increase demands on our health care system and decrease the quality of life for patients with COPD. Anxious or depressed patients have higher 30-day readmission rates and less frequent outpatient follow-up than COPD patients without these mental comorbidities.⁶ Patients with comorbidities tend to have a higher prevalence of systemic symptoms independent of COPD severity,⁷ exhibit poorer physical and social functioning,¹³ and experience greater impairment of quality of life than patients with lung dysfunction alone.^1,14 Patients with GAD or MDD have a 43% increased risk of any adverse COPD outcome, which can include exacerbations, COPD-related diagnoses (eg, emphysema), new anxiety or depression events, and death.¹¹ Specifically, the risk of a COPD exacerbation rises by 31% in patients with comorbid GAD or MDD, and risk of death in those with comorbid MDD increases by 83%.¹¹

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease, instead of a psychological disorder.

GAD or MDD with COPD increases health care utilization and costs per patient when compared with patients who have COPD alone.⁹ Annual physician visits, emergency-room visits, and hospitalizations for any cause are higher in anxious or depressed COPD patients, and they have a 77% increased chance annually of a COPD-related hospitalization.⁹ Annual COPD-related health care costs for patients with GAD or MDD are significantly higher than the average COPD-related costs for patients without depression or anxiety, leading to significantly increased all-cause health care costs: $28,961 vs $22,512.⁹ Addressing and managing comorbid GAD or MDD in COPD patients could substantially reduce health care costs.

Be vigilant for anxiety, depression—even when COPD is mild

One reason comorbid GAD or MDD may be overlooked and underdiagnosed is that the symptoms can overlap those of COPD. In cases where suspicion of GAD or MDD is warranted, providers must keep separate the diagnostic inquiries for COPD and these comorbidities.⁶

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease instead of a psychological disorder. Differentiating the 2 processes becomes more difficult with patients younger than 60 years, as they are more likely to experience symptoms of GAD or MDD than older patients, regardless of COPD severity.¹⁵ Therefore, when assessing COPD patients, physicians need to be more vigilant for anxiety and depression, even in the mildest cases.¹⁴

Several methods exist for assessing anxiety and depression, including the Generalized Anxiety Disorder Screener 7 (GAD-7) and the Patient Health Questionnaire (PHQ) 2 or 9.¹⁶ All PHQ and GAD-7 screeners and translations are downloadable from www.phqscreeners.com/select-screener and permission is not required to reproduce, translate, display, or distribute them (FIGURE).¹⁶ Other anxiety and depression screening instruments are also available.

No one method has been shown to be most effective for rapid screening, and the physician’s comfort level or familiarity with a particular assessment tool may guide selection. One advantage of short screening instruments is that they can be incorporated into electronic health records for easy use across continuity visits. Although routine screening for these mental comorbidities takes slightly more time—especially in high-volume family practice clinics—it needs to become standard practice to protect patients’ quality of life.

Managing psychiatric conditions in COPD

Treatment for GAD and MDD in COPD is often suboptimal and may diminish a patient’s quality of life. In one study, COPD patients with a mental illness were 46% less likely than those with COPD alone to receive medications such as short- or long-acting bronchodilators and inhaled corticosteroids.¹⁷ Therapy for both the physiologic abnormalities and mental disturbances should be initiated promptly to maintain an acceptable state of health.

Pharmacotherapy. Reluctance to give traditional psychiatric medications to COPD patients contributes to the under-treatment of mental comorbidities. While benzodiazepines are generally not recommended—especially in severe COPD cases due to their sedative effect on respiratory drive—alternatives such as buspirone, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) have been shown to effectively reduce GAD, MDD, and dyspnea in these patients^5,14(TABLE^18,19).

Non-pharmacotherapy approaches. Having patients apply behavioral-modification principles to their own behavior²⁰ has been proposed as a standard of care in the treatment of COPD.²¹ A recent systematic review found that self-management (behavior change) interventions in patients with COPD improved health-related quality of life, reduced hospital admissions, and helped alleviate dyspnea.²² While that review could not make clear recommendations regarding the most effective form and content of self-management in COPD,²² patient engagement and motivation in creating treatment goals are considered critical ingredients for effective self-management.²¹

Motivational Interviewing (MI) is an evidence-based behavioral approach designed for patients who are ambivalent about or resistant to change.²³ MI works by supporting a patient’s autonomy and by activating his/her own internal motivation for change or adherence to treatment. In MI, the physician’s involvement with the patient relies on collaboration, evocation, and autonomy, rather than confrontation, education, and authority. MI involves exploration more than exhortation, and support rather than persuasion or argument. The overall goal of MI is to increase intrinsic motivation so that change arises from within and serves the patient’s goals and values.²³

The risk of a COPD exacerbation rises by 31% in patients with comorbid anxiety or depression; risk of death in those with comorbid depression increases by 83%.

Benzo, et al, provide a very detailed description of a self-management process that includes MI.²¹ Their protocol proved to be feasible in severe COPD and helped increase patient engagement and commitment to self-management.²¹ This finding and similar evidence of MI’s effectiveness in a variety of other health conditions suggest that pharmacotherapy and cognitive-behavior therapy can be delivered in combination with an MI approach.

Self-management depends on a patient’s readiness to implement behavioral changes. Patients engaged in unhealthy behavior may be reluctant to change at a particular time, so the physician may focus efforts on such behaviors as self-monitoring or examining values that may lead to future behavior change.

For example, a patient may not want to stop smoking, but the physician’s willingness to ask about smoking in subsequent visits may catch the patient at a time when motivation has changed—eg, perhaps there is a new child in the home, prompting a recognition that smoking is now inconsistent with one’s values and can be resolved with smoking cessation. Awareness of an individual’s baseline behavior and readiness to change assists physicians and other health professionals in tailoring interventions for the most favorable outcome.

Several other non-pharmacologic methods to reduce symptoms of GAD and MDD in patients with COPD have been studied and supported by the literature.

• Progressive muscle relaxation, stress management, biofeedback, and guided imagery have been shown to decrease symptoms of anxiety, dyspnea, and airway obstruction.^5,14
• Pulmonary rehabilitation programs including psychotherapy sessions have also relieved symptoms of GAD and MDD for patients with COPD.
• Programs that include physiotherapy, physical exercise (arm and leg exercise, aerobic conditioning, flexibility training), patient education, and psychotherapy sessions have significantly lowered GAD and MDD scores when compared with similar rehabilitation programs not offering psychotherapy.²⁴
• Cognitive-behavioral therapy has been variably effective in treating comorbid GAD and MDD, with studies citing either superiority⁵ or equivalence²⁵ to COPD education alone.

Increasingly, psychologists have been integrated into primary care with implementation of the Patient-Centered Medical Home.²⁶ However, if primary care physicians do not have behavioral specialists available, they can contact the American Psychological Association, their state psychological association, or professional organizations, such as the Society of Behavioral Medicine, for referral to professionals trained in behavioral self-management skills.

Initiation of treatment, whether pharmacological or non-pharmacological, and emphasis on self-management of the disease can greatly improve patients' perceptions of their condition and overall quality of life.

CASE › The patient screens positive for GAD and you give him a prescription for venlafaxine to begin immediately. Using an MI approach, you help the patient clarify that being more engaged with his family is important to him. Acknowledging that your recommendations are consistent with his values, the patient agrees to pursue pulmonary rehabilitation and, with the aid of a behavioral health specialist, learn self-management techniques for medication adherence and social reengagement.

CORRESPONDENCE
Ms. Sydney Marsh, 3009 S 35th Ave., Omaha, NE 68105; sydneymarsh@creighton.edu.

CASE › A 66-year-old man you have seen many times for issues related to his chronic obstructive pulmonary disease (COPD) comes in to your clinic for a routine visit. He has been taking budesonide/formoterol twice a day for the last 3 years; however, he has not always been compliant with his medications and has been hospitalized within the last 6 months for disease exacerbations. Today, he says he has difficulty falling asleep and often becomes short of breath, even when physically inactive. His wife, who is accompanying him today, tells you he has become increasingly distant over the past few months and is not as engaged at family outings, which he attributes to labored breathing. They’re both concerned about this change and ask for advice.

Despite the increased awareness that generalized anxiety disorder (GAD) and major depressive disorder (MDD) are common comorbidities of COPD, they remain underdiagnosed and undertreated in patients with COPD. The results are increased rates of symptom exacerbation and rehospitalization.¹ Family physicians, who are the primary caregivers for most patients with the disease,² can maximize patients’ quality of life by recognizing comorbid mental illness, motivating and engaging patients in their disease management, and initiating appropriate treatment.

Anxiety and depression in COPD: A 2-way street

Several studies have assessed the prevalence of psychological disorders in patients with COPD. Affective disorders, mainly GAD and MDD, are the ones most commonly associated with poor COPD prognoses.^3,4 GAD is at least 3 times more prevalent in patients with COPD than in the general US population,⁵ reaching upwards of 55%.^1,6 Prevalence of MDD is also high, affecting approximately 40% of patients with the disease.¹

GAD and MDD are more prevalent as comorbidities of COPD than they are with other chronic diseases such as orthopedic conditions, pulmonary tuberculosis, hypertension and heart disease, stroke, diabetes, and cancer.^5,7-9 Patients with COPD, more so than patients with other serious chronic diseases, report heightened edginess, anxiousness, tiredness, distractibility, and irritability,⁵ perhaps owing in part to breathlessness and “air hunger.”¹⁰

The connection between COPD and GAD or MDD is not unidirectional, with progression of lung disease exacerbating its psychological comorbidities. The interaction is reciprocal, as clarified by Atlantis, et al, in a 2013 systematic review and meta-analysis that assessed key variables in the development of COPD and GAD or MDD.¹¹

COPD increases the risk of MDD, which is associated with increased tobacco consumption, poor adherence with COPD medications, and decreased physical activity.¹¹ Compounding the problem of inactivity is the fact that COPD—particularly longstanding disease—can lead to volume reductions in the anterior cingulate cortex of patients, which correlates with a persistent fear of performing physical activity.¹² MDD in the setting of COPD also complicates the already complex interplay between nicotine dependence and attempts at smoking cessation.¹¹

GAD/MDD worsens COPD outcomes

Comorbid GAD and MDD increase demands on our health care system and decrease the quality of life for patients with COPD. Anxious or depressed patients have higher 30-day readmission rates and less frequent outpatient follow-up than COPD patients without these mental comorbidities.⁶ Patients with comorbidities tend to have a higher prevalence of systemic symptoms independent of COPD severity,⁷ exhibit poorer physical and social functioning,¹³ and experience greater impairment of quality of life than patients with lung dysfunction alone.^1,14 Patients with GAD or MDD have a 43% increased risk of any adverse COPD outcome, which can include exacerbations, COPD-related diagnoses (eg, emphysema), new anxiety or depression events, and death.¹¹ Specifically, the risk of a COPD exacerbation rises by 31% in patients with comorbid GAD or MDD, and risk of death in those with comorbid MDD increases by 83%.¹¹

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease, instead of a psychological disorder.

GAD or MDD with COPD increases health care utilization and costs per patient when compared with patients who have COPD alone.⁹ Annual physician visits, emergency-room visits, and hospitalizations for any cause are higher in anxious or depressed COPD patients, and they have a 77% increased chance annually of a COPD-related hospitalization.⁹ Annual COPD-related health care costs for patients with GAD or MDD are significantly higher than the average COPD-related costs for patients without depression or anxiety, leading to significantly increased all-cause health care costs: $28,961 vs $22,512.⁹ Addressing and managing comorbid GAD or MDD in COPD patients could substantially reduce health care costs.

Be vigilant for anxiety, depression—even when COPD is mild

One reason comorbid GAD or MDD may be overlooked and underdiagnosed is that the symptoms can overlap those of COPD. In cases where suspicion of GAD or MDD is warranted, providers must keep separate the diagnostic inquiries for COPD and these comorbidities.⁶

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease instead of a psychological disorder. Differentiating the 2 processes becomes more difficult with patients younger than 60 years, as they are more likely to experience symptoms of GAD or MDD than older patients, regardless of COPD severity.¹⁵ Therefore, when assessing COPD patients, physicians need to be more vigilant for anxiety and depression, even in the mildest cases.¹⁴

Several methods exist for assessing anxiety and depression, including the Generalized Anxiety Disorder Screener 7 (GAD-7) and the Patient Health Questionnaire (PHQ) 2 or 9.¹⁶ All PHQ and GAD-7 screeners and translations are downloadable from www.phqscreeners.com/select-screener and permission is not required to reproduce, translate, display, or distribute them (FIGURE).¹⁶ Other anxiety and depression screening instruments are also available.

No one method has been shown to be most effective for rapid screening, and the physician’s comfort level or familiarity with a particular assessment tool may guide selection. One advantage of short screening instruments is that they can be incorporated into electronic health records for easy use across continuity visits. Although routine screening for these mental comorbidities takes slightly more time—especially in high-volume family practice clinics—it needs to become standard practice to protect patients’ quality of life.

Managing psychiatric conditions in COPD

Treatment for GAD and MDD in COPD is often suboptimal and may diminish a patient’s quality of life. In one study, COPD patients with a mental illness were 46% less likely than those with COPD alone to receive medications such as short- or long-acting bronchodilators and inhaled corticosteroids.¹⁷ Therapy for both the physiologic abnormalities and mental disturbances should be initiated promptly to maintain an acceptable state of health.

Pharmacotherapy. Reluctance to give traditional psychiatric medications to COPD patients contributes to the under-treatment of mental comorbidities. While benzodiazepines are generally not recommended—especially in severe COPD cases due to their sedative effect on respiratory drive—alternatives such as buspirone, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) have been shown to effectively reduce GAD, MDD, and dyspnea in these patients^5,14(TABLE^18,19).

Non-pharmacotherapy approaches. Having patients apply behavioral-modification principles to their own behavior²⁰ has been proposed as a standard of care in the treatment of COPD.²¹ A recent systematic review found that self-management (behavior change) interventions in patients with COPD improved health-related quality of life, reduced hospital admissions, and helped alleviate dyspnea.²² While that review could not make clear recommendations regarding the most effective form and content of self-management in COPD,²² patient engagement and motivation in creating treatment goals are considered critical ingredients for effective self-management.²¹

Motivational Interviewing (MI) is an evidence-based behavioral approach designed for patients who are ambivalent about or resistant to change.²³ MI works by supporting a patient’s autonomy and by activating his/her own internal motivation for change or adherence to treatment. In MI, the physician’s involvement with the patient relies on collaboration, evocation, and autonomy, rather than confrontation, education, and authority. MI involves exploration more than exhortation, and support rather than persuasion or argument. The overall goal of MI is to increase intrinsic motivation so that change arises from within and serves the patient’s goals and values.²³

The risk of a COPD exacerbation rises by 31% in patients with comorbid anxiety or depression; risk of death in those with comorbid depression increases by 83%.

Benzo, et al, provide a very detailed description of a self-management process that includes MI.²¹ Their protocol proved to be feasible in severe COPD and helped increase patient engagement and commitment to self-management.²¹ This finding and similar evidence of MI’s effectiveness in a variety of other health conditions suggest that pharmacotherapy and cognitive-behavior therapy can be delivered in combination with an MI approach.

Self-management depends on a patient’s readiness to implement behavioral changes. Patients engaged in unhealthy behavior may be reluctant to change at a particular time, so the physician may focus efforts on such behaviors as self-monitoring or examining values that may lead to future behavior change.

For example, a patient may not want to stop smoking, but the physician’s willingness to ask about smoking in subsequent visits may catch the patient at a time when motivation has changed—eg, perhaps there is a new child in the home, prompting a recognition that smoking is now inconsistent with one’s values and can be resolved with smoking cessation. Awareness of an individual’s baseline behavior and readiness to change assists physicians and other health professionals in tailoring interventions for the most favorable outcome.

Several other non-pharmacologic methods to reduce symptoms of GAD and MDD in patients with COPD have been studied and supported by the literature.

• Progressive muscle relaxation, stress management, biofeedback, and guided imagery have been shown to decrease symptoms of anxiety, dyspnea, and airway obstruction.^5,14
• Pulmonary rehabilitation programs including psychotherapy sessions have also relieved symptoms of GAD and MDD for patients with COPD.
• Programs that include physiotherapy, physical exercise (arm and leg exercise, aerobic conditioning, flexibility training), patient education, and psychotherapy sessions have significantly lowered GAD and MDD scores when compared with similar rehabilitation programs not offering psychotherapy.²⁴
• Cognitive-behavioral therapy has been variably effective in treating comorbid GAD and MDD, with studies citing either superiority⁵ or equivalence²⁵ to COPD education alone.

Increasingly, psychologists have been integrated into primary care with implementation of the Patient-Centered Medical Home.²⁶ However, if primary care physicians do not have behavioral specialists available, they can contact the American Psychological Association, their state psychological association, or professional organizations, such as the Society of Behavioral Medicine, for referral to professionals trained in behavioral self-management skills.

Initiation of treatment, whether pharmacological or non-pharmacological, and emphasis on self-management of the disease can greatly improve patients' perceptions of their condition and overall quality of life.

CASE › The patient screens positive for GAD and you give him a prescription for venlafaxine to begin immediately. Using an MI approach, you help the patient clarify that being more engaged with his family is important to him. Acknowledging that your recommendations are consistent with his values, the patient agrees to pursue pulmonary rehabilitation and, with the aid of a behavioral health specialist, learn self-management techniques for medication adherence and social reengagement.

CORRESPONDENCE
Ms. Sydney Marsh, 3009 S 35th Ave., Omaha, NE 68105; sydneymarsh@creighton.edu.

CASE › A 66-year-old man you have seen many times for issues related to his chronic obstructive pulmonary disease (COPD) comes in to your clinic for a routine visit. He has been taking budesonide/formoterol twice a day for the last 3 years; however, he has not always been compliant with his medications and has been hospitalized within the last 6 months for disease exacerbations. Today, he says he has difficulty falling asleep and often becomes short of breath, even when physically inactive. His wife, who is accompanying him today, tells you he has become increasingly distant over the past few months and is not as engaged at family outings, which he attributes to labored breathing. They’re both concerned about this change and ask for advice.

Despite the increased awareness that generalized anxiety disorder (GAD) and major depressive disorder (MDD) are common comorbidities of COPD, they remain underdiagnosed and undertreated in patients with COPD. The results are increased rates of symptom exacerbation and rehospitalization.¹ Family physicians, who are the primary caregivers for most patients with the disease,² can maximize patients’ quality of life by recognizing comorbid mental illness, motivating and engaging patients in their disease management, and initiating appropriate treatment.

Anxiety and depression in COPD: A 2-way street

Several studies have assessed the prevalence of psychological disorders in patients with COPD. Affective disorders, mainly GAD and MDD, are the ones most commonly associated with poor COPD prognoses.^3,4 GAD is at least 3 times more prevalent in patients with COPD than in the general US population,⁵ reaching upwards of 55%.^1,6 Prevalence of MDD is also high, affecting approximately 40% of patients with the disease.¹

GAD and MDD are more prevalent as comorbidities of COPD than they are with other chronic diseases such as orthopedic conditions, pulmonary tuberculosis, hypertension and heart disease, stroke, diabetes, and cancer.^5,7-9 Patients with COPD, more so than patients with other serious chronic diseases, report heightened edginess, anxiousness, tiredness, distractibility, and irritability,⁵ perhaps owing in part to breathlessness and “air hunger.”¹⁰

The connection between COPD and GAD or MDD is not unidirectional, with progression of lung disease exacerbating its psychological comorbidities. The interaction is reciprocal, as clarified by Atlantis, et al, in a 2013 systematic review and meta-analysis that assessed key variables in the development of COPD and GAD or MDD.¹¹

COPD increases the risk of MDD, which is associated with increased tobacco consumption, poor adherence with COPD medications, and decreased physical activity.¹¹ Compounding the problem of inactivity is the fact that COPD—particularly longstanding disease—can lead to volume reductions in the anterior cingulate cortex of patients, which correlates with a persistent fear of performing physical activity.¹² MDD in the setting of COPD also complicates the already complex interplay between nicotine dependence and attempts at smoking cessation.¹¹

GAD/MDD worsens COPD outcomes

Comorbid GAD and MDD increase demands on our health care system and decrease the quality of life for patients with COPD. Anxious or depressed patients have higher 30-day readmission rates and less frequent outpatient follow-up than COPD patients without these mental comorbidities.⁶ Patients with comorbidities tend to have a higher prevalence of systemic symptoms independent of COPD severity,⁷ exhibit poorer physical and social functioning,¹³ and experience greater impairment of quality of life than patients with lung dysfunction alone.^1,14 Patients with GAD or MDD have a 43% increased risk of any adverse COPD outcome, which can include exacerbations, COPD-related diagnoses (eg, emphysema), new anxiety or depression events, and death.¹¹ Specifically, the risk of a COPD exacerbation rises by 31% in patients with comorbid GAD or MDD, and risk of death in those with comorbid MDD increases by 83%.¹¹

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease, instead of a psychological disorder.

GAD or MDD with COPD increases health care utilization and costs per patient when compared with patients who have COPD alone.⁹ Annual physician visits, emergency-room visits, and hospitalizations for any cause are higher in anxious or depressed COPD patients, and they have a 77% increased chance annually of a COPD-related hospitalization.⁹ Annual COPD-related health care costs for patients with GAD or MDD are significantly higher than the average COPD-related costs for patients without depression or anxiety, leading to significantly increased all-cause health care costs: $28,961 vs $22,512.⁹ Addressing and managing comorbid GAD or MDD in COPD patients could substantially reduce health care costs.

Be vigilant for anxiety, depression—even when COPD is mild

One reason comorbid GAD or MDD may be overlooked and underdiagnosed is that the symptoms can overlap those of COPD. In cases where suspicion of GAD or MDD is warranted, providers must keep separate the diagnostic inquiries for COPD and these comorbidities.⁶

Somatic symptoms of anxiety, such as hyperventilation, shortness of breath, and sweating, may easily be attributed to pulmonary disease instead of a psychological disorder. Differentiating the 2 processes becomes more difficult with patients younger than 60 years, as they are more likely to experience symptoms of GAD or MDD than older patients, regardless of COPD severity.¹⁵ Therefore, when assessing COPD patients, physicians need to be more vigilant for anxiety and depression, even in the mildest cases.¹⁴

Several methods exist for assessing anxiety and depression, including the Generalized Anxiety Disorder Screener 7 (GAD-7) and the Patient Health Questionnaire (PHQ) 2 or 9.¹⁶ All PHQ and GAD-7 screeners and translations are downloadable from www.phqscreeners.com/select-screener and permission is not required to reproduce, translate, display, or distribute them (FIGURE).¹⁶ Other anxiety and depression screening instruments are also available.

No one method has been shown to be most effective for rapid screening, and the physician’s comfort level or familiarity with a particular assessment tool may guide selection. One advantage of short screening instruments is that they can be incorporated into electronic health records for easy use across continuity visits. Although routine screening for these mental comorbidities takes slightly more time—especially in high-volume family practice clinics—it needs to become standard practice to protect patients’ quality of life.

Managing psychiatric conditions in COPD

Treatment for GAD and MDD in COPD is often suboptimal and may diminish a patient’s quality of life. In one study, COPD patients with a mental illness were 46% less likely than those with COPD alone to receive medications such as short- or long-acting bronchodilators and inhaled corticosteroids.¹⁷ Therapy for both the physiologic abnormalities and mental disturbances should be initiated promptly to maintain an acceptable state of health.

Pharmacotherapy. Reluctance to give traditional psychiatric medications to COPD patients contributes to the under-treatment of mental comorbidities. While benzodiazepines are generally not recommended—especially in severe COPD cases due to their sedative effect on respiratory drive—alternatives such as buspirone, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) have been shown to effectively reduce GAD, MDD, and dyspnea in these patients^5,14(TABLE^18,19).

Non-pharmacotherapy approaches. Having patients apply behavioral-modification principles to their own behavior²⁰ has been proposed as a standard of care in the treatment of COPD.²¹ A recent systematic review found that self-management (behavior change) interventions in patients with COPD improved health-related quality of life, reduced hospital admissions, and helped alleviate dyspnea.²² While that review could not make clear recommendations regarding the most effective form and content of self-management in COPD,²² patient engagement and motivation in creating treatment goals are considered critical ingredients for effective self-management.²¹

Motivational Interviewing (MI) is an evidence-based behavioral approach designed for patients who are ambivalent about or resistant to change.²³ MI works by supporting a patient’s autonomy and by activating his/her own internal motivation for change or adherence to treatment. In MI, the physician’s involvement with the patient relies on collaboration, evocation, and autonomy, rather than confrontation, education, and authority. MI involves exploration more than exhortation, and support rather than persuasion or argument. The overall goal of MI is to increase intrinsic motivation so that change arises from within and serves the patient’s goals and values.²³

The risk of a COPD exacerbation rises by 31% in patients with comorbid anxiety or depression; risk of death in those with comorbid depression increases by 83%.

Benzo, et al, provide a very detailed description of a self-management process that includes MI.²¹ Their protocol proved to be feasible in severe COPD and helped increase patient engagement and commitment to self-management.²¹ This finding and similar evidence of MI’s effectiveness in a variety of other health conditions suggest that pharmacotherapy and cognitive-behavior therapy can be delivered in combination with an MI approach.

Self-management depends on a patient’s readiness to implement behavioral changes. Patients engaged in unhealthy behavior may be reluctant to change at a particular time, so the physician may focus efforts on such behaviors as self-monitoring or examining values that may lead to future behavior change.

For example, a patient may not want to stop smoking, but the physician’s willingness to ask about smoking in subsequent visits may catch the patient at a time when motivation has changed—eg, perhaps there is a new child in the home, prompting a recognition that smoking is now inconsistent with one’s values and can be resolved with smoking cessation. Awareness of an individual’s baseline behavior and readiness to change assists physicians and other health professionals in tailoring interventions for the most favorable outcome.

Several other non-pharmacologic methods to reduce symptoms of GAD and MDD in patients with COPD have been studied and supported by the literature.

• Progressive muscle relaxation, stress management, biofeedback, and guided imagery have been shown to decrease symptoms of anxiety, dyspnea, and airway obstruction.^5,14
• Pulmonary rehabilitation programs including psychotherapy sessions have also relieved symptoms of GAD and MDD for patients with COPD.
• Programs that include physiotherapy, physical exercise (arm and leg exercise, aerobic conditioning, flexibility training), patient education, and psychotherapy sessions have significantly lowered GAD and MDD scores when compared with similar rehabilitation programs not offering psychotherapy.²⁴
• Cognitive-behavioral therapy has been variably effective in treating comorbid GAD and MDD, with studies citing either superiority⁵ or equivalence²⁵ to COPD education alone.

Increasingly, psychologists have been integrated into primary care with implementation of the Patient-Centered Medical Home.²⁶ However, if primary care physicians do not have behavioral specialists available, they can contact the American Psychological Association, their state psychological association, or professional organizations, such as the Society of Behavioral Medicine, for referral to professionals trained in behavioral self-management skills.

Initiation of treatment, whether pharmacological or non-pharmacological, and emphasis on self-management of the disease can greatly improve patients' perceptions of their condition and overall quality of life.

CASE › The patient screens positive for GAD and you give him a prescription for venlafaxine to begin immediately. Using an MI approach, you help the patient clarify that being more engaged with his family is important to him. Acknowledging that your recommendations are consistent with his values, the patient agrees to pursue pulmonary rehabilitation and, with the aid of a behavioral health specialist, learn self-management techniques for medication adherence and social reengagement.

CORRESPONDENCE
Ms. Sydney Marsh, 3009 S 35th Ave., Omaha, NE 68105; sydneymarsh@creighton.edu.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

New guidelines decrease the minimum duration of dual-antiplatelet therapy (DAPT) to as little as 3 months after drug-eluting stent placement in certain lower-risk patients with coronary artery disease.

The updated recommendations harmonize and replace six other guidelines, and apply to everolimus and zotarolimus stents, not Cypher or Taxus stents, said Dr. Eric R. Bates, who helped author the American College of Cardiology/American Heart Association Focused Update. “The emphasis is on balancing ischemic risk versus bleeding risk. The recommendations give clinicians guideline coverage to make personalized DAPT recommendations,” he said in an interview.

The guidance reflects recent evidence that shorter duration (3-6 months) of DAPT, compared with the standard 12 months of therapy does not increase the risk of stent thrombosis and potentially lessens bleeding risk in select patients. Other studies of an additional 18 or 36 months of DAPT found a decrease in the risk of MI and stent thrombosis, at the cost of greater risk of bleeding. Thus, the updated guidelines call for “a thoughtful assessment of the benefit-risk ratio, integration of study data, and consideration of patient preference” when selecting duration of DAPT. “In general, shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk, whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk,” the authors wrote, led by Dr. Glenn N. Levineof Baylor College of Medicine, Houston (J Am Coll Cardiol. 2016 Mar 29. doi: 10.1016/j.jacc.2016.03.512).

The recommendations define DAPT as combination therapy with aspirin and a P2Y12 receptor inhibitor – that is, clopidogrel, prasugrel, or ticagrelor. “When indicated, ticagrelor and prasugrel have a Class IIa preference over clopidogrel,” Dr. Bates said. The recommended daily dose of aspirin is 81 mg (range, 75-100 mg), which is usually continued indefinitely, regardless of how long patients receive dual therapy.

The shortened durations of dual-antiplatelet therapy include several scenarios. For elective percutaneous coronary intervention, the former Class I recommendation for 12 months of DAPT has been reduced to 6 months, with a Class IIb recommendation for either longer treatment or shorter (3-month) treatment, Dr. Bates, professor of medicine at the University of Michigan Health System in Ann Arbor, said. For patients with acute coronary syndrome, the guidelines retain the Class I recommendation for 12 months of DAPT, but also add a Class IIb recommendation for longer or shorter (6 months) DAPT.

The guidelines also include a new Class IIb recommendation for 12 months of DAPT started early after coronary artery bypass graft in patients with stable ischemic heart disease. This strategy “may be reasonable to improve vein graft patency” in these patients, the recommendations state.

The guidance clarifies previous recommendations on the timing of elective noncardiac surgery, and assigns Class IIb support for consideration of such surgeries starting 3 months after implantation of drug-eluting stents, if the risks of delaying surgery outweigh the expected risk of stent thrombosis when it is necessary to stop P2Y12 inhibitor therapy.

©Svisio/Thinkstock

The recommendations now distinguish between B and C levels of evidence to increase granularity, according to Dr. Bates. The document updates recommendations on duration of DAPT across six previously published guidelines – the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention (PCI); the 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery; the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease; the 2013ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction; the 2014 ACC/AHA Guideline for Non-ST-Elevation Acute Coronary Syndromes, and the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery.

The extensive evidence review that informed guideline development was simultaneously reported by Dr. John Bittl at Munroe Regional Medical Center in Ocala, Fla., and his colleagues. The investigators synthesized evidence from 11 randomized controlled trials of more than 33,000 patients who received mainly newer generation stents. They also reviewed a randomized controlled trial of more than 21,000 patients with stable ischemic heart disease who were more than 1 year post-MI, and a post hoc analysis of a trial of more than 15,000 such patients.

These reviews uncovered “moderately strong evidence” that prolonged DAPT after implantation of newer generation drug-eluting stents “entails a trade-off between reductions in stent thrombosis and MI and increases in major hemorrhage,” Dr. Bittl and his colleagues wrote. Likewise, they found moderately strong evidence that prolonged DAPT helps prevent cardiovascular events at the cost of increased bleeding in patients whose coronary thrombotic risk stemmed from prior MI, not stent implantation. They found weak evidence of increased mortality in stent patients who received prolonged DAPT.

Dr. Bates reported consulting relationships with Merck and AstraZeneca. Eight other coauthors disclosed financial relationships with a number of pharmaceutical or device companies. Dr. Glenn Levine and seven coauthors disclosed no relationships with industry.

New guidelines decrease the minimum duration of dual-antiplatelet therapy (DAPT) to as little as 3 months after drug-eluting stent placement in certain lower-risk patients with coronary artery disease.

The updated recommendations harmonize and replace six other guidelines, and apply to everolimus and zotarolimus stents, not Cypher or Taxus stents, said Dr. Eric R. Bates, who helped author the American College of Cardiology/American Heart Association Focused Update. “The emphasis is on balancing ischemic risk versus bleeding risk. The recommendations give clinicians guideline coverage to make personalized DAPT recommendations,” he said in an interview.

The guidance reflects recent evidence that shorter duration (3-6 months) of DAPT, compared with the standard 12 months of therapy does not increase the risk of stent thrombosis and potentially lessens bleeding risk in select patients. Other studies of an additional 18 or 36 months of DAPT found a decrease in the risk of MI and stent thrombosis, at the cost of greater risk of bleeding. Thus, the updated guidelines call for “a thoughtful assessment of the benefit-risk ratio, integration of study data, and consideration of patient preference” when selecting duration of DAPT. “In general, shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk, whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk,” the authors wrote, led by Dr. Glenn N. Levineof Baylor College of Medicine, Houston (J Am Coll Cardiol. 2016 Mar 29. doi: 10.1016/j.jacc.2016.03.512).

The recommendations define DAPT as combination therapy with aspirin and a P2Y12 receptor inhibitor – that is, clopidogrel, prasugrel, or ticagrelor. “When indicated, ticagrelor and prasugrel have a Class IIa preference over clopidogrel,” Dr. Bates said. The recommended daily dose of aspirin is 81 mg (range, 75-100 mg), which is usually continued indefinitely, regardless of how long patients receive dual therapy.

The shortened durations of dual-antiplatelet therapy include several scenarios. For elective percutaneous coronary intervention, the former Class I recommendation for 12 months of DAPT has been reduced to 6 months, with a Class IIb recommendation for either longer treatment or shorter (3-month) treatment, Dr. Bates, professor of medicine at the University of Michigan Health System in Ann Arbor, said. For patients with acute coronary syndrome, the guidelines retain the Class I recommendation for 12 months of DAPT, but also add a Class IIb recommendation for longer or shorter (6 months) DAPT.

The guidelines also include a new Class IIb recommendation for 12 months of DAPT started early after coronary artery bypass graft in patients with stable ischemic heart disease. This strategy “may be reasonable to improve vein graft patency” in these patients, the recommendations state.

The guidance clarifies previous recommendations on the timing of elective noncardiac surgery, and assigns Class IIb support for consideration of such surgeries starting 3 months after implantation of drug-eluting stents, if the risks of delaying surgery outweigh the expected risk of stent thrombosis when it is necessary to stop P2Y12 inhibitor therapy.

©Svisio/Thinkstock

The recommendations now distinguish between B and C levels of evidence to increase granularity, according to Dr. Bates. The document updates recommendations on duration of DAPT across six previously published guidelines – the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention (PCI); the 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery; the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease; the 2013ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction; the 2014 ACC/AHA Guideline for Non-ST-Elevation Acute Coronary Syndromes, and the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery.

The extensive evidence review that informed guideline development was simultaneously reported by Dr. John Bittl at Munroe Regional Medical Center in Ocala, Fla., and his colleagues. The investigators synthesized evidence from 11 randomized controlled trials of more than 33,000 patients who received mainly newer generation stents. They also reviewed a randomized controlled trial of more than 21,000 patients with stable ischemic heart disease who were more than 1 year post-MI, and a post hoc analysis of a trial of more than 15,000 such patients.

These reviews uncovered “moderately strong evidence” that prolonged DAPT after implantation of newer generation drug-eluting stents “entails a trade-off between reductions in stent thrombosis and MI and increases in major hemorrhage,” Dr. Bittl and his colleagues wrote. Likewise, they found moderately strong evidence that prolonged DAPT helps prevent cardiovascular events at the cost of increased bleeding in patients whose coronary thrombotic risk stemmed from prior MI, not stent implantation. They found weak evidence of increased mortality in stent patients who received prolonged DAPT.

Dr. Bates reported consulting relationships with Merck and AstraZeneca. Eight other coauthors disclosed financial relationships with a number of pharmaceutical or device companies. Dr. Glenn Levine and seven coauthors disclosed no relationships with industry.

New guidelines decrease the minimum duration of dual-antiplatelet therapy (DAPT) to as little as 3 months after drug-eluting stent placement in certain lower-risk patients with coronary artery disease.

The updated recommendations harmonize and replace six other guidelines, and apply to everolimus and zotarolimus stents, not Cypher or Taxus stents, said Dr. Eric R. Bates, who helped author the American College of Cardiology/American Heart Association Focused Update. “The emphasis is on balancing ischemic risk versus bleeding risk. The recommendations give clinicians guideline coverage to make personalized DAPT recommendations,” he said in an interview.

The guidance reflects recent evidence that shorter duration (3-6 months) of DAPT, compared with the standard 12 months of therapy does not increase the risk of stent thrombosis and potentially lessens bleeding risk in select patients. Other studies of an additional 18 or 36 months of DAPT found a decrease in the risk of MI and stent thrombosis, at the cost of greater risk of bleeding. Thus, the updated guidelines call for “a thoughtful assessment of the benefit-risk ratio, integration of study data, and consideration of patient preference” when selecting duration of DAPT. “In general, shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk, whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk,” the authors wrote, led by Dr. Glenn N. Levineof Baylor College of Medicine, Houston (J Am Coll Cardiol. 2016 Mar 29. doi: 10.1016/j.jacc.2016.03.512).

The recommendations define DAPT as combination therapy with aspirin and a P2Y12 receptor inhibitor – that is, clopidogrel, prasugrel, or ticagrelor. “When indicated, ticagrelor and prasugrel have a Class IIa preference over clopidogrel,” Dr. Bates said. The recommended daily dose of aspirin is 81 mg (range, 75-100 mg), which is usually continued indefinitely, regardless of how long patients receive dual therapy.

The shortened durations of dual-antiplatelet therapy include several scenarios. For elective percutaneous coronary intervention, the former Class I recommendation for 12 months of DAPT has been reduced to 6 months, with a Class IIb recommendation for either longer treatment or shorter (3-month) treatment, Dr. Bates, professor of medicine at the University of Michigan Health System in Ann Arbor, said. For patients with acute coronary syndrome, the guidelines retain the Class I recommendation for 12 months of DAPT, but also add a Class IIb recommendation for longer or shorter (6 months) DAPT.

The guidelines also include a new Class IIb recommendation for 12 months of DAPT started early after coronary artery bypass graft in patients with stable ischemic heart disease. This strategy “may be reasonable to improve vein graft patency” in these patients, the recommendations state.

The guidance clarifies previous recommendations on the timing of elective noncardiac surgery, and assigns Class IIb support for consideration of such surgeries starting 3 months after implantation of drug-eluting stents, if the risks of delaying surgery outweigh the expected risk of stent thrombosis when it is necessary to stop P2Y12 inhibitor therapy.

©Svisio/Thinkstock

The recommendations now distinguish between B and C levels of evidence to increase granularity, according to Dr. Bates. The document updates recommendations on duration of DAPT across six previously published guidelines – the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention (PCI); the 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery; the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease; the 2013ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction; the 2014 ACC/AHA Guideline for Non-ST-Elevation Acute Coronary Syndromes, and the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery.

The extensive evidence review that informed guideline development was simultaneously reported by Dr. John Bittl at Munroe Regional Medical Center in Ocala, Fla., and his colleagues. The investigators synthesized evidence from 11 randomized controlled trials of more than 33,000 patients who received mainly newer generation stents. They also reviewed a randomized controlled trial of more than 21,000 patients with stable ischemic heart disease who were more than 1 year post-MI, and a post hoc analysis of a trial of more than 15,000 such patients.

These reviews uncovered “moderately strong evidence” that prolonged DAPT after implantation of newer generation drug-eluting stents “entails a trade-off between reductions in stent thrombosis and MI and increases in major hemorrhage,” Dr. Bittl and his colleagues wrote. Likewise, they found moderately strong evidence that prolonged DAPT helps prevent cardiovascular events at the cost of increased bleeding in patients whose coronary thrombotic risk stemmed from prior MI, not stent implantation. They found weak evidence of increased mortality in stent patients who received prolonged DAPT.

Dr. Bates reported consulting relationships with Merck and AstraZeneca. Eight other coauthors disclosed financial relationships with a number of pharmaceutical or device companies. Dr. Glenn Levine and seven coauthors disclosed no relationships with industry.

Philadelphia, PA –The Society of Hospital Medicine (SHM)’s Physician in Training Committee recently announced the 2016 Student Hospitalist Scholar Grant recipients, who earned the scholarship based on their abilities and interest in hospital medicine, prior educational training and dedication to scholarly activity in the field.

SHM’s Physician in Training Committee launched the scholarship program for medical students in 2015 to inspire future hospitalists to play an active role in transforming healthcare and revolutionizing patient care. For more information on the Student Hospitalist Scholar Grant. All information for trainees interested in hospital medicine can be found at, SHM’s website dedicated to resources for those interested in a career as a hospitalist. To join SHM as a medical student member at no cost.

The four grant recipients, each of whom is a student member of SHM, will use their funding to complete scholarly work with an active SHM member as their mentor on a project related to patient safety or quality improvement. The 2016 Student Hospitalist Scholarship recipients are:

• Shane Ali, University of Texas School of Medicine at San Antonio

  Mentor: Nilam Soni, MD

  Project: Pleural Fluid Echogenicity by Ultrasound Imaging and Computer Based Pixilation to Determine Transudative vs. Exudative Effusions

  Project Site: University of Texas Health Science Center, San Antonio, Texas

• Joseph Moo-Young, University of North Carolina School of Medicine

  Mentor: Ria Dancel, MD, FHM

  Project: Analysis and Optimization of the Inpatient Pediatric Discharge Process

  Project Site: University of North Carolina Children's Hospital

• Aram Namavar, Loyola University Chicago – Stritch School of Medicine

  Mentor: Nasim Afsar, MD, SFHM

  Project: Evaluation of Decisional Conflict as a Simple Tool to assess Risk for Readmission

  Location of Project: Ronald Reagan UCLA Medical Center, Los Angeles, CA

• Haverly Snyder, Medical College of Wisconsin

  Mentor: Kathlyn Fletcher, MD, FHM

  Project: The Trauma of Hospitalization: Identifying Causes and Potential Solutions

  Project Site: Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin

Throughout their experiences, the student scholars will be blogging about their projects on SHM’s official blog, The Hospital Leader, and posting in the Future of Hospital Medicine community on the Hospital Medicine Exchange (HMX), SHM’s online member engagement platform. Upon completing their projects, the students will draft progress reports and submit their findings as abstracts for the Research, Innovations and Clinical Vignettes (RIV) competition at Hospital Medicine 2017, SHM’s annual meeting to be held in Las Vegas in May.

Philadelphia, PA –The Society of Hospital Medicine (SHM)’s Physician in Training Committee recently announced the 2016 Student Hospitalist Scholar Grant recipients, who earned the scholarship based on their abilities and interest in hospital medicine, prior educational training and dedication to scholarly activity in the field.

SHM’s Physician in Training Committee launched the scholarship program for medical students in 2015 to inspire future hospitalists to play an active role in transforming healthcare and revolutionizing patient care. For more information on the Student Hospitalist Scholar Grant. All information for trainees interested in hospital medicine can be found at, SHM’s website dedicated to resources for those interested in a career as a hospitalist. To join SHM as a medical student member at no cost.

The four grant recipients, each of whom is a student member of SHM, will use their funding to complete scholarly work with an active SHM member as their mentor on a project related to patient safety or quality improvement. The 2016 Student Hospitalist Scholarship recipients are:

• Shane Ali, University of Texas School of Medicine at San Antonio

  Mentor: Nilam Soni, MD

  Project: Pleural Fluid Echogenicity by Ultrasound Imaging and Computer Based Pixilation to Determine Transudative vs. Exudative Effusions

  Project Site: University of Texas Health Science Center, San Antonio, Texas

• Joseph Moo-Young, University of North Carolina School of Medicine

  Mentor: Ria Dancel, MD, FHM

  Project: Analysis and Optimization of the Inpatient Pediatric Discharge Process

  Project Site: University of North Carolina Children's Hospital

• Aram Namavar, Loyola University Chicago – Stritch School of Medicine

  Mentor: Nasim Afsar, MD, SFHM

  Project: Evaluation of Decisional Conflict as a Simple Tool to assess Risk for Readmission

  Location of Project: Ronald Reagan UCLA Medical Center, Los Angeles, CA

• Haverly Snyder, Medical College of Wisconsin

  Mentor: Kathlyn Fletcher, MD, FHM

  Project: The Trauma of Hospitalization: Identifying Causes and Potential Solutions

  Project Site: Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin

Throughout their experiences, the student scholars will be blogging about their projects on SHM’s official blog, The Hospital Leader, and posting in the Future of Hospital Medicine community on the Hospital Medicine Exchange (HMX), SHM’s online member engagement platform. Upon completing their projects, the students will draft progress reports and submit their findings as abstracts for the Research, Innovations and Clinical Vignettes (RIV) competition at Hospital Medicine 2017, SHM’s annual meeting to be held in Las Vegas in May.

Philadelphia, PA –The Society of Hospital Medicine (SHM)’s Physician in Training Committee recently announced the 2016 Student Hospitalist Scholar Grant recipients, who earned the scholarship based on their abilities and interest in hospital medicine, prior educational training and dedication to scholarly activity in the field.

SHM’s Physician in Training Committee launched the scholarship program for medical students in 2015 to inspire future hospitalists to play an active role in transforming healthcare and revolutionizing patient care. For more information on the Student Hospitalist Scholar Grant. All information for trainees interested in hospital medicine can be found at, SHM’s website dedicated to resources for those interested in a career as a hospitalist. To join SHM as a medical student member at no cost.

The four grant recipients, each of whom is a student member of SHM, will use their funding to complete scholarly work with an active SHM member as their mentor on a project related to patient safety or quality improvement. The 2016 Student Hospitalist Scholarship recipients are:

• Shane Ali, University of Texas School of Medicine at San Antonio

  Mentor: Nilam Soni, MD

  Project: Pleural Fluid Echogenicity by Ultrasound Imaging and Computer Based Pixilation to Determine Transudative vs. Exudative Effusions

  Project Site: University of Texas Health Science Center, San Antonio, Texas

• Joseph Moo-Young, University of North Carolina School of Medicine

  Mentor: Ria Dancel, MD, FHM

  Project: Analysis and Optimization of the Inpatient Pediatric Discharge Process

  Project Site: University of North Carolina Children's Hospital

• Aram Namavar, Loyola University Chicago – Stritch School of Medicine

  Mentor: Nasim Afsar, MD, SFHM

  Project: Evaluation of Decisional Conflict as a Simple Tool to assess Risk for Readmission

  Location of Project: Ronald Reagan UCLA Medical Center, Los Angeles, CA

• Haverly Snyder, Medical College of Wisconsin

  Mentor: Kathlyn Fletcher, MD, FHM

  Project: The Trauma of Hospitalization: Identifying Causes and Potential Solutions

  Project Site: Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin

Throughout their experiences, the student scholars will be blogging about their projects on SHM’s official blog, The Hospital Leader, and posting in the Future of Hospital Medicine community on the Hospital Medicine Exchange (HMX), SHM’s online member engagement platform. Upon completing their projects, the students will draft progress reports and submit their findings as abstracts for the Research, Innovations and Clinical Vignettes (RIV) competition at Hospital Medicine 2017, SHM’s annual meeting to be held in Las Vegas in May.

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

Progression to structural damage occurs slowly among patients with early axial spondyloarthritis and more often takes place in current smokers, HLAB27 carriers, and those with signs of inflammation on MRI, according to new observations from the French DESIR cohort study.

The findings help to establish risk factors for early progression of nonradiographic axial spondyloarthritis (nr-axSpA) to radiographic disease, said Dr. Maxime Dougados of the department of rheumatology at Cochin Hospital, Paris, and his colleagues (Arthritis Rheumatol. 2016 Mar 18. doi: 10.1002/art.39666).

The study involved 449 patients with recent-onset inflammatory back pain who were participating in the multicenter, longitudinal DESIR study and had x-rays available at baseline and 2-year follow-up.

A total of 16 (4.9%) out of 326 patients who did not fulfill the modified New York criteria (mNY) at baseline progressed from nonradiographic to radiographic axSpA over the 2-year study period.

Of the 123 patients who met the mNY criteria at baseline, 7 (5.7%) no longer met the criteria at follow-up.

Independent factors found to influence the odds of progressing to radiographic axSpA were smoking status (odds ratio, 3.3; 95% confidence interval, 1.0-11.5), HLAB27 positivity (OR, 12.6; 95% CI, 2.3-274), and the presence of inflammation at MRI in the sacroiliac joints (SIJs) at baseline (OR, 48.8; 95% CI, 9.3-904), a multivariate analysis showed.

However, when the authors defined radiographic progression as “a worsening of at least one grade in at least one SIJ,” HLAB27 positivity (OR, 1.68; 95% CI, 0.8-3.71, P = .02), MRI positivity (OR, 5.85; 95% CI, 2.38-15.37, P less than .001), and baseline structural damage at SIJs on pelvic x-rays (OR, 6.35; 95% CI, 2.14-18.88; P less than .001) were predictors of radiographic disease progression. Another analysis confirmed those as risk factors even when the definition of progression also required a final absolute grade of at least 2 in the worsened SIJs.

When the authors considered the change in total score (based on the mean of two readers), only HLAB27 positivity and baseline MRI positivity were highlighted as independent predictors of disease progression. In this analysis, HLAB27 positivity and inflammation on MRI had grading score increases of 0.41 (P = .014) and 1.03 (P less than .001), respectively.

Unlike other studies, the researchers did not see a clear relationship between abnormal C-reactive protein at baseline and radiographic progression.

The findings suggest that, in early SpA, “structural progression does exist but is quite small and observed in a small number of patients,” the study authors wrote.

The authors noted that their findings should be “interpreted with caution” because they were based on a small number of patients, and additional studies with a longer-follow-up period are needed to confirm the findings.

The DESIR cohort was sponsored by the Department de la recherché Clinique et du Development de l’Assistance Publique-Hopitaux de Paris. An unrestricted grant from Pfizer was allocated for the 10 years of follow-up.

Progression to structural damage occurs slowly among patients with early axial spondyloarthritis and more often takes place in current smokers, HLAB27 carriers, and those with signs of inflammation on MRI, according to new observations from the French DESIR cohort study.

The findings help to establish risk factors for early progression of nonradiographic axial spondyloarthritis (nr-axSpA) to radiographic disease, said Dr. Maxime Dougados of the department of rheumatology at Cochin Hospital, Paris, and his colleagues (Arthritis Rheumatol. 2016 Mar 18. doi: 10.1002/art.39666).

The study involved 449 patients with recent-onset inflammatory back pain who were participating in the multicenter, longitudinal DESIR study and had x-rays available at baseline and 2-year follow-up.

A total of 16 (4.9%) out of 326 patients who did not fulfill the modified New York criteria (mNY) at baseline progressed from nonradiographic to radiographic axSpA over the 2-year study period.

Of the 123 patients who met the mNY criteria at baseline, 7 (5.7%) no longer met the criteria at follow-up.

Independent factors found to influence the odds of progressing to radiographic axSpA were smoking status (odds ratio, 3.3; 95% confidence interval, 1.0-11.5), HLAB27 positivity (OR, 12.6; 95% CI, 2.3-274), and the presence of inflammation at MRI in the sacroiliac joints (SIJs) at baseline (OR, 48.8; 95% CI, 9.3-904), a multivariate analysis showed.

However, when the authors defined radiographic progression as “a worsening of at least one grade in at least one SIJ,” HLAB27 positivity (OR, 1.68; 95% CI, 0.8-3.71, P = .02), MRI positivity (OR, 5.85; 95% CI, 2.38-15.37, P less than .001), and baseline structural damage at SIJs on pelvic x-rays (OR, 6.35; 95% CI, 2.14-18.88; P less than .001) were predictors of radiographic disease progression. Another analysis confirmed those as risk factors even when the definition of progression also required a final absolute grade of at least 2 in the worsened SIJs.

When the authors considered the change in total score (based on the mean of two readers), only HLAB27 positivity and baseline MRI positivity were highlighted as independent predictors of disease progression. In this analysis, HLAB27 positivity and inflammation on MRI had grading score increases of 0.41 (P = .014) and 1.03 (P less than .001), respectively.

Unlike other studies, the researchers did not see a clear relationship between abnormal C-reactive protein at baseline and radiographic progression.

The findings suggest that, in early SpA, “structural progression does exist but is quite small and observed in a small number of patients,” the study authors wrote.

The authors noted that their findings should be “interpreted with caution” because they were based on a small number of patients, and additional studies with a longer-follow-up period are needed to confirm the findings.

The DESIR cohort was sponsored by the Department de la recherché Clinique et du Development de l’Assistance Publique-Hopitaux de Paris. An unrestricted grant from Pfizer was allocated for the 10 years of follow-up.

Progression to structural damage occurs slowly among patients with early axial spondyloarthritis and more often takes place in current smokers, HLAB27 carriers, and those with signs of inflammation on MRI, according to new observations from the French DESIR cohort study.

The findings help to establish risk factors for early progression of nonradiographic axial spondyloarthritis (nr-axSpA) to radiographic disease, said Dr. Maxime Dougados of the department of rheumatology at Cochin Hospital, Paris, and his colleagues (Arthritis Rheumatol. 2016 Mar 18. doi: 10.1002/art.39666).

The study involved 449 patients with recent-onset inflammatory back pain who were participating in the multicenter, longitudinal DESIR study and had x-rays available at baseline and 2-year follow-up.

A total of 16 (4.9%) out of 326 patients who did not fulfill the modified New York criteria (mNY) at baseline progressed from nonradiographic to radiographic axSpA over the 2-year study period.

Of the 123 patients who met the mNY criteria at baseline, 7 (5.7%) no longer met the criteria at follow-up.

Independent factors found to influence the odds of progressing to radiographic axSpA were smoking status (odds ratio, 3.3; 95% confidence interval, 1.0-11.5), HLAB27 positivity (OR, 12.6; 95% CI, 2.3-274), and the presence of inflammation at MRI in the sacroiliac joints (SIJs) at baseline (OR, 48.8; 95% CI, 9.3-904), a multivariate analysis showed.

However, when the authors defined radiographic progression as “a worsening of at least one grade in at least one SIJ,” HLAB27 positivity (OR, 1.68; 95% CI, 0.8-3.71, P = .02), MRI positivity (OR, 5.85; 95% CI, 2.38-15.37, P less than .001), and baseline structural damage at SIJs on pelvic x-rays (OR, 6.35; 95% CI, 2.14-18.88; P less than .001) were predictors of radiographic disease progression. Another analysis confirmed those as risk factors even when the definition of progression also required a final absolute grade of at least 2 in the worsened SIJs.

When the authors considered the change in total score (based on the mean of two readers), only HLAB27 positivity and baseline MRI positivity were highlighted as independent predictors of disease progression. In this analysis, HLAB27 positivity and inflammation on MRI had grading score increases of 0.41 (P = .014) and 1.03 (P less than .001), respectively.

Unlike other studies, the researchers did not see a clear relationship between abnormal C-reactive protein at baseline and radiographic progression.

The findings suggest that, in early SpA, “structural progression does exist but is quite small and observed in a small number of patients,” the study authors wrote.

The authors noted that their findings should be “interpreted with caution” because they were based on a small number of patients, and additional studies with a longer-follow-up period are needed to confirm the findings.

The DESIR cohort was sponsored by the Department de la recherché Clinique et du Development de l’Assistance Publique-Hopitaux de Paris. An unrestricted grant from Pfizer was allocated for the 10 years of follow-up.