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Acute liver failure in the ED
Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.
In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.
But delays in the decision to go ahead with a liver transplant can lead to death.
A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.
In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.
“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”
As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.
Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.
Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.
Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation.
Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.
Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.
In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.
But delays in the decision to go ahead with a liver transplant can lead to death.
A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.
In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.
“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”
As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.
Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.
Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.
Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation.
Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.
Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.
In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.
But delays in the decision to go ahead with a liver transplant can lead to death.
A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.
In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.
“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”
As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.
Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.
Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.
Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation.
Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.
FROM THE AMERICAN JOURNAL OF EMERGENCY MEDICINE
Cancer immunotherapy seen repigmenting gray hair
Patients on immunotherapy treatments for lung cancer have experienced repigmentation of their formerly gray hair, according to a new report. Moreover, researchers say, all but one of the patients experiencing this effect also responded well to the therapy, suggesting that hair repigmentation could potentially serve as a marker of treatment response.
In a case series published online July 12 in JAMA Dermatology (2017. doi: 10.1001/jamadermatol.2017.2106), Noelia Rivera, MD, of the Universitat Autònoma de Barcelona and her colleagues report findings from 14 patients (13 male, mean age 65) receiving anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) therapies to treat squamous cell lung cancer or lung adenocarcinoma, with most (11) receiving nivolumab (Opdivo). All but one patient experienced a diffuse darkening of the hair to resemble its previous color, while the remaining patient’s repigmentation occurred in patches.
Dr. Rivera and her colleagues wrote in their analysis that gray hair follicles “still preserve a reduced number of differentiated and functioning melanocytes located in the hair bulb. This reduced number of melanocytes may explain the possibility of [repigmentation] under appropriate conditions.” But, there are competing theories as to why this should occur with cancer immunotherapy, they noted. One is that the drugs’ inhibition of proinflammatory cytokines acts as negative regulators of melanogenesis. Another is that melanocytes in hair follicles are activated through inflammatory mediators. Of the patients with hair repigmentation in the study, only one, who was being treated with nivolumab for lung squamous cell carcinoma, had disease progression. This patient was discontinued after four treatment sessions and died. The other 13 patients saw either stable disease or a partial response.
The study received no outside funding, but two investigators disclosed financial relationships with pharmaceutical manufacturers.
Patients on immunotherapy treatments for lung cancer have experienced repigmentation of their formerly gray hair, according to a new report. Moreover, researchers say, all but one of the patients experiencing this effect also responded well to the therapy, suggesting that hair repigmentation could potentially serve as a marker of treatment response.
In a case series published online July 12 in JAMA Dermatology (2017. doi: 10.1001/jamadermatol.2017.2106), Noelia Rivera, MD, of the Universitat Autònoma de Barcelona and her colleagues report findings from 14 patients (13 male, mean age 65) receiving anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) therapies to treat squamous cell lung cancer or lung adenocarcinoma, with most (11) receiving nivolumab (Opdivo). All but one patient experienced a diffuse darkening of the hair to resemble its previous color, while the remaining patient’s repigmentation occurred in patches.
Dr. Rivera and her colleagues wrote in their analysis that gray hair follicles “still preserve a reduced number of differentiated and functioning melanocytes located in the hair bulb. This reduced number of melanocytes may explain the possibility of [repigmentation] under appropriate conditions.” But, there are competing theories as to why this should occur with cancer immunotherapy, they noted. One is that the drugs’ inhibition of proinflammatory cytokines acts as negative regulators of melanogenesis. Another is that melanocytes in hair follicles are activated through inflammatory mediators. Of the patients with hair repigmentation in the study, only one, who was being treated with nivolumab for lung squamous cell carcinoma, had disease progression. This patient was discontinued after four treatment sessions and died. The other 13 patients saw either stable disease or a partial response.
The study received no outside funding, but two investigators disclosed financial relationships with pharmaceutical manufacturers.
Patients on immunotherapy treatments for lung cancer have experienced repigmentation of their formerly gray hair, according to a new report. Moreover, researchers say, all but one of the patients experiencing this effect also responded well to the therapy, suggesting that hair repigmentation could potentially serve as a marker of treatment response.
In a case series published online July 12 in JAMA Dermatology (2017. doi: 10.1001/jamadermatol.2017.2106), Noelia Rivera, MD, of the Universitat Autònoma de Barcelona and her colleagues report findings from 14 patients (13 male, mean age 65) receiving anti–programmed cell death 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1) therapies to treat squamous cell lung cancer or lung adenocarcinoma, with most (11) receiving nivolumab (Opdivo). All but one patient experienced a diffuse darkening of the hair to resemble its previous color, while the remaining patient’s repigmentation occurred in patches.
Dr. Rivera and her colleagues wrote in their analysis that gray hair follicles “still preserve a reduced number of differentiated and functioning melanocytes located in the hair bulb. This reduced number of melanocytes may explain the possibility of [repigmentation] under appropriate conditions.” But, there are competing theories as to why this should occur with cancer immunotherapy, they noted. One is that the drugs’ inhibition of proinflammatory cytokines acts as negative regulators of melanogenesis. Another is that melanocytes in hair follicles are activated through inflammatory mediators. Of the patients with hair repigmentation in the study, only one, who was being treated with nivolumab for lung squamous cell carcinoma, had disease progression. This patient was discontinued after four treatment sessions and died. The other 13 patients saw either stable disease or a partial response.
The study received no outside funding, but two investigators disclosed financial relationships with pharmaceutical manufacturers.
FROM JAMA DERMATOLOGY
Key clinical point:
Major finding: Of 52 patients, 14 patients saw a diffuse restoration of their original hair color during the course of treatment. All but 1 of these also saw a robust treatment response.
Data source: A case series drawn from a single-center cohort of 52 lung cancer patients treated with anti–PD-1 and anti–PD-L1 and monitored for cutaneous effects.
Disclosures: Two coauthors disclosed financial relationships with several drug manufacturers.
Add-on aripiprazole shows modest improvement over bupropion in depression
In men with major depressive disorder (MMD) who were not responding well to an antidepressant treatment, adding aripiprazole resulted in a modest increase in the likelihood of remission, compared with switching to bupropion monotherapy, according to results from a new randomized study.
The findings, published online July 11 in JAMA, come from a randomized, single-blinded trial enrolling more than 1,500 Veterans Health Administration patients (85% men; mean age, 54) with persistent MDD symptoms despite a trial of at least 1 antidepressant drug (JAMA. 2017;318[2]:132-45.).
The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, led by Somaia Mohamed, MD, PhD, of the VA Connecticut Healthcare System in West Haven, Conn., and carried out at 35 Veterans Health Administration treatment centers, was designed to help answer some of the lingering questions about augmentation strategies that the landmark, federally funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, from 2006, could not answer.
While the STAR*D investigators found bupropion to be an effective switching and augmentation agent in people who had failed citalopram monotherapy, the study was not powered to compare results for switching and augmentation. Nor did STAR*D include augmentation with atypical antipsychotics such as aripiprazole, a treatment strategy that was not yet in wide use.
The VAST-D study also differed from most depression trials in that most of the patients were men. The main outcome was clinical remission within 12 weeks of initiating one of the three treatment strategies. Subjects were randomized to augmentation of current treatment with aripiprazole 2-15 mg (n = 505) or bupropion 150-400 mg (n = 506) or were switched from current treatment to bupropion monotherapy (n = 511).
Remission rates during the first 12 weeks were 22% for patients switched from their current drug to bupropion, 27% for those who augmented treatment with bupropion, and 29% for those who augmented treatment with aripiprazole, though the difference in remission reached statistical significance only for the adjunctive aripiprazole group vs. the bupropion monotherapy group (relative risk, 1.30; 95% confidence interval, 1.05-1.60; P = .02).
Clinical response, as measured using two validated scoring systems, was higher (74%) in the aripiprazole group at 12 weeks, compared with the bupropion only (62%) or bupropion augmentation (66%) groups, a difference that reached statistical significance. Anxiety was more commonly reported among patients in the bupropion groups, while somnolence, akathisia, and weight gain were more frequently reported among patients treated with aripiprazole.
Though aripiprazole augmentation was seen associated with a higher rate of remission and greater response, Dr. Mohamed and her colleagues cautioned that, “given the small effect size and adverse effects” associated with the atypical antipsychotic drug, “further analysis, including cost-effectiveness, is needed to understand the net utility of this approach.”
The Department of Veterans Affairs sponsored the study. Bristol-Myers Squibb provided aripiprazole to investigators. Of the study’s 16 listed coauthors, 5 reported financial relationships with Bristol-Myers Squibb or other manufacturers.
“The modest advantage of aripiprazole augmentation over the two other treatment options in the VAST-D study suggests that this approach should be considered earlier by clinicians for patients with MDD who have an inadequate response to antidepressant therapies,” Maurizio Fava, MD, wrote in an editorial accompanying the study published by JAMA.
He also pointed out that the demographic makeup of the patients study was largely male, which is significantly different “from the usual study population in large trials of MDD, in which women typically far exceed the proportion of male study participants, as was the case with STAR*D.”
Dr. Fava cited the differences in the proportion of patients with posttraumatic stress disorder in the VAST-D and STAR*D study. In VAST-D, 44%-48% had PTSD, compared with a rate of 17% in the STAR*D cohort. “Did such enrichment potentially favor one of the treatment options of VAST-D? Although a placebo-controlled study of bupropion in chronic PTSD showed no benefit of this therapy, a meta-analysis of eight randomized, double-blind, placebo-controlled clinical trials of atypical antipsychotics for the treatment of PTSD found that these agents may be superior to placebo,” Dr. Fava wrote.
Finally, he cited the differences in mean age of onset of MDD in the two studies. In the VAST-D study, the mean age of onset ranged from 36 to 38 years and compared with a mean age of onset of 25 in STAR*D. “The older age of onset of MDD in the VAST-D study suggests that, in many cases, the MDD may have been secondary to other psychiatric conditions, such as PTSD. Therefore, there might be some significant neurobiological differences between the two populations,” Dr. Fava wrote (JAMA. 2017;318[2]:126-8).
Dr. Fava is affiliated with the division of clinical research at Massachusetts General Hospital, Boston. He reported financial relationships with numerous pharmaceutical companies.
“The modest advantage of aripiprazole augmentation over the two other treatment options in the VAST-D study suggests that this approach should be considered earlier by clinicians for patients with MDD who have an inadequate response to antidepressant therapies,” Maurizio Fava, MD, wrote in an editorial accompanying the study published by JAMA.
He also pointed out that the demographic makeup of the patients study was largely male, which is significantly different “from the usual study population in large trials of MDD, in which women typically far exceed the proportion of male study participants, as was the case with STAR*D.”
Dr. Fava cited the differences in the proportion of patients with posttraumatic stress disorder in the VAST-D and STAR*D study. In VAST-D, 44%-48% had PTSD, compared with a rate of 17% in the STAR*D cohort. “Did such enrichment potentially favor one of the treatment options of VAST-D? Although a placebo-controlled study of bupropion in chronic PTSD showed no benefit of this therapy, a meta-analysis of eight randomized, double-blind, placebo-controlled clinical trials of atypical antipsychotics for the treatment of PTSD found that these agents may be superior to placebo,” Dr. Fava wrote.
Finally, he cited the differences in mean age of onset of MDD in the two studies. In the VAST-D study, the mean age of onset ranged from 36 to 38 years and compared with a mean age of onset of 25 in STAR*D. “The older age of onset of MDD in the VAST-D study suggests that, in many cases, the MDD may have been secondary to other psychiatric conditions, such as PTSD. Therefore, there might be some significant neurobiological differences between the two populations,” Dr. Fava wrote (JAMA. 2017;318[2]:126-8).
Dr. Fava is affiliated with the division of clinical research at Massachusetts General Hospital, Boston. He reported financial relationships with numerous pharmaceutical companies.
“The modest advantage of aripiprazole augmentation over the two other treatment options in the VAST-D study suggests that this approach should be considered earlier by clinicians for patients with MDD who have an inadequate response to antidepressant therapies,” Maurizio Fava, MD, wrote in an editorial accompanying the study published by JAMA.
He also pointed out that the demographic makeup of the patients study was largely male, which is significantly different “from the usual study population in large trials of MDD, in which women typically far exceed the proportion of male study participants, as was the case with STAR*D.”
Dr. Fava cited the differences in the proportion of patients with posttraumatic stress disorder in the VAST-D and STAR*D study. In VAST-D, 44%-48% had PTSD, compared with a rate of 17% in the STAR*D cohort. “Did such enrichment potentially favor one of the treatment options of VAST-D? Although a placebo-controlled study of bupropion in chronic PTSD showed no benefit of this therapy, a meta-analysis of eight randomized, double-blind, placebo-controlled clinical trials of atypical antipsychotics for the treatment of PTSD found that these agents may be superior to placebo,” Dr. Fava wrote.
Finally, he cited the differences in mean age of onset of MDD in the two studies. In the VAST-D study, the mean age of onset ranged from 36 to 38 years and compared with a mean age of onset of 25 in STAR*D. “The older age of onset of MDD in the VAST-D study suggests that, in many cases, the MDD may have been secondary to other psychiatric conditions, such as PTSD. Therefore, there might be some significant neurobiological differences between the two populations,” Dr. Fava wrote (JAMA. 2017;318[2]:126-8).
Dr. Fava is affiliated with the division of clinical research at Massachusetts General Hospital, Boston. He reported financial relationships with numerous pharmaceutical companies.
In men with major depressive disorder (MMD) who were not responding well to an antidepressant treatment, adding aripiprazole resulted in a modest increase in the likelihood of remission, compared with switching to bupropion monotherapy, according to results from a new randomized study.
The findings, published online July 11 in JAMA, come from a randomized, single-blinded trial enrolling more than 1,500 Veterans Health Administration patients (85% men; mean age, 54) with persistent MDD symptoms despite a trial of at least 1 antidepressant drug (JAMA. 2017;318[2]:132-45.).
The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, led by Somaia Mohamed, MD, PhD, of the VA Connecticut Healthcare System in West Haven, Conn., and carried out at 35 Veterans Health Administration treatment centers, was designed to help answer some of the lingering questions about augmentation strategies that the landmark, federally funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, from 2006, could not answer.
While the STAR*D investigators found bupropion to be an effective switching and augmentation agent in people who had failed citalopram monotherapy, the study was not powered to compare results for switching and augmentation. Nor did STAR*D include augmentation with atypical antipsychotics such as aripiprazole, a treatment strategy that was not yet in wide use.
The VAST-D study also differed from most depression trials in that most of the patients were men. The main outcome was clinical remission within 12 weeks of initiating one of the three treatment strategies. Subjects were randomized to augmentation of current treatment with aripiprazole 2-15 mg (n = 505) or bupropion 150-400 mg (n = 506) or were switched from current treatment to bupropion monotherapy (n = 511).
Remission rates during the first 12 weeks were 22% for patients switched from their current drug to bupropion, 27% for those who augmented treatment with bupropion, and 29% for those who augmented treatment with aripiprazole, though the difference in remission reached statistical significance only for the adjunctive aripiprazole group vs. the bupropion monotherapy group (relative risk, 1.30; 95% confidence interval, 1.05-1.60; P = .02).
Clinical response, as measured using two validated scoring systems, was higher (74%) in the aripiprazole group at 12 weeks, compared with the bupropion only (62%) or bupropion augmentation (66%) groups, a difference that reached statistical significance. Anxiety was more commonly reported among patients in the bupropion groups, while somnolence, akathisia, and weight gain were more frequently reported among patients treated with aripiprazole.
Though aripiprazole augmentation was seen associated with a higher rate of remission and greater response, Dr. Mohamed and her colleagues cautioned that, “given the small effect size and adverse effects” associated with the atypical antipsychotic drug, “further analysis, including cost-effectiveness, is needed to understand the net utility of this approach.”
The Department of Veterans Affairs sponsored the study. Bristol-Myers Squibb provided aripiprazole to investigators. Of the study’s 16 listed coauthors, 5 reported financial relationships with Bristol-Myers Squibb or other manufacturers.
In men with major depressive disorder (MMD) who were not responding well to an antidepressant treatment, adding aripiprazole resulted in a modest increase in the likelihood of remission, compared with switching to bupropion monotherapy, according to results from a new randomized study.
The findings, published online July 11 in JAMA, come from a randomized, single-blinded trial enrolling more than 1,500 Veterans Health Administration patients (85% men; mean age, 54) with persistent MDD symptoms despite a trial of at least 1 antidepressant drug (JAMA. 2017;318[2]:132-45.).
The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, led by Somaia Mohamed, MD, PhD, of the VA Connecticut Healthcare System in West Haven, Conn., and carried out at 35 Veterans Health Administration treatment centers, was designed to help answer some of the lingering questions about augmentation strategies that the landmark, federally funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, from 2006, could not answer.
While the STAR*D investigators found bupropion to be an effective switching and augmentation agent in people who had failed citalopram monotherapy, the study was not powered to compare results for switching and augmentation. Nor did STAR*D include augmentation with atypical antipsychotics such as aripiprazole, a treatment strategy that was not yet in wide use.
The VAST-D study also differed from most depression trials in that most of the patients were men. The main outcome was clinical remission within 12 weeks of initiating one of the three treatment strategies. Subjects were randomized to augmentation of current treatment with aripiprazole 2-15 mg (n = 505) or bupropion 150-400 mg (n = 506) or were switched from current treatment to bupropion monotherapy (n = 511).
Remission rates during the first 12 weeks were 22% for patients switched from their current drug to bupropion, 27% for those who augmented treatment with bupropion, and 29% for those who augmented treatment with aripiprazole, though the difference in remission reached statistical significance only for the adjunctive aripiprazole group vs. the bupropion monotherapy group (relative risk, 1.30; 95% confidence interval, 1.05-1.60; P = .02).
Clinical response, as measured using two validated scoring systems, was higher (74%) in the aripiprazole group at 12 weeks, compared with the bupropion only (62%) or bupropion augmentation (66%) groups, a difference that reached statistical significance. Anxiety was more commonly reported among patients in the bupropion groups, while somnolence, akathisia, and weight gain were more frequently reported among patients treated with aripiprazole.
Though aripiprazole augmentation was seen associated with a higher rate of remission and greater response, Dr. Mohamed and her colleagues cautioned that, “given the small effect size and adverse effects” associated with the atypical antipsychotic drug, “further analysis, including cost-effectiveness, is needed to understand the net utility of this approach.”
The Department of Veterans Affairs sponsored the study. Bristol-Myers Squibb provided aripiprazole to investigators. Of the study’s 16 listed coauthors, 5 reported financial relationships with Bristol-Myers Squibb or other manufacturers.
FROM JAMA
Key clinical point: Aripiprazole added to a current antidepressant was associated with a modestly higher remission rate among men with MDD than was switching to bupropion monotherapy.
Major finding: Remission by 12 weeks was 28.9% among patients receiving add-on aripiprazole, vs. 22.3% for bupropion alone (RR, 1.30; 95% CI, 1.05-1.60; P = 0.02).
Data source: A randomized, single-blinded multicenter trial enrolling more than 1,500 patients (85% men) with persistent MDD despite treatment.
Disclosures: The Veterans Health Administration sponsored the study. One of the study drugs was donated by a manufacturer, and 5 of 16 coauthors disclosed financial conflicts of interest.
Common malaria diagnostic test also can predict treatment-related anemia
While the drug artesunate remains the gold standard for patients with severe Plasmodium falciparum malaria, it also can induce anemia within days or weeks of starting treatment.
In research published online in Science Translational Medicine, a team of researchers led by Papa Alioune Ndour, PhD, of the Université Paris Descartes, presented findings on how a cheap, widely available diagnostic test for malaria infection can be used, under a modified protocol, to predict a form of anemia known as postartesunate delayed hemolysis (PADH) (Sci Transl Med. 2017 Jul 5;9[397]. pii: eaaf9377).
Dr. Ndour and his colleagues discovered, studying prospective cohorts of 95 artesunate-treated malaria patients in Bangladesh and 53 in France, that, if they administered an HRP2 test on day 3 of treatment, a positive result predicted PADH with 89% sensitivity and 73% specificity. However, while the diagnostic test uses a whole blood sample, blood must be diluted 1:500 for the same test to predict PADH. The investigators also studied a comparison cohort of 49 quinine-treated patients in France, in whom HRP2 persistence was much lower.
Using the HRP2-based tests for PADH prediction is more complex than using it for malaria diagnosis, as blood samples must be diluted and because assessment “involves a quantitative element” to determine whether once-infected red blood cells have reached a concentration associated with a high risk of hemolysis, Dr. Ndour and his colleagues cautioned.
“Future large prospective studies will more precisely determine the robustness of prediction in different geographic and logistical settings,” the researchers wrote in their analysis.
The study was funded by the Bill & Melinda Gates Foundation, the French National Research Agency, and the Wellcome Trust. Five investigators, including Dr. Ndour, disclosed research grants from pharmaceutical firms for artesunate studies, two disclosed advisory board relationships with a Sigma Tau Laboratories, and another reported industry funding for anemia research related to artesunate.
While the drug artesunate remains the gold standard for patients with severe Plasmodium falciparum malaria, it also can induce anemia within days or weeks of starting treatment.
In research published online in Science Translational Medicine, a team of researchers led by Papa Alioune Ndour, PhD, of the Université Paris Descartes, presented findings on how a cheap, widely available diagnostic test for malaria infection can be used, under a modified protocol, to predict a form of anemia known as postartesunate delayed hemolysis (PADH) (Sci Transl Med. 2017 Jul 5;9[397]. pii: eaaf9377).
Dr. Ndour and his colleagues discovered, studying prospective cohorts of 95 artesunate-treated malaria patients in Bangladesh and 53 in France, that, if they administered an HRP2 test on day 3 of treatment, a positive result predicted PADH with 89% sensitivity and 73% specificity. However, while the diagnostic test uses a whole blood sample, blood must be diluted 1:500 for the same test to predict PADH. The investigators also studied a comparison cohort of 49 quinine-treated patients in France, in whom HRP2 persistence was much lower.
Using the HRP2-based tests for PADH prediction is more complex than using it for malaria diagnosis, as blood samples must be diluted and because assessment “involves a quantitative element” to determine whether once-infected red blood cells have reached a concentration associated with a high risk of hemolysis, Dr. Ndour and his colleagues cautioned.
“Future large prospective studies will more precisely determine the robustness of prediction in different geographic and logistical settings,” the researchers wrote in their analysis.
The study was funded by the Bill & Melinda Gates Foundation, the French National Research Agency, and the Wellcome Trust. Five investigators, including Dr. Ndour, disclosed research grants from pharmaceutical firms for artesunate studies, two disclosed advisory board relationships with a Sigma Tau Laboratories, and another reported industry funding for anemia research related to artesunate.
While the drug artesunate remains the gold standard for patients with severe Plasmodium falciparum malaria, it also can induce anemia within days or weeks of starting treatment.
In research published online in Science Translational Medicine, a team of researchers led by Papa Alioune Ndour, PhD, of the Université Paris Descartes, presented findings on how a cheap, widely available diagnostic test for malaria infection can be used, under a modified protocol, to predict a form of anemia known as postartesunate delayed hemolysis (PADH) (Sci Transl Med. 2017 Jul 5;9[397]. pii: eaaf9377).
Dr. Ndour and his colleagues discovered, studying prospective cohorts of 95 artesunate-treated malaria patients in Bangladesh and 53 in France, that, if they administered an HRP2 test on day 3 of treatment, a positive result predicted PADH with 89% sensitivity and 73% specificity. However, while the diagnostic test uses a whole blood sample, blood must be diluted 1:500 for the same test to predict PADH. The investigators also studied a comparison cohort of 49 quinine-treated patients in France, in whom HRP2 persistence was much lower.
Using the HRP2-based tests for PADH prediction is more complex than using it for malaria diagnosis, as blood samples must be diluted and because assessment “involves a quantitative element” to determine whether once-infected red blood cells have reached a concentration associated with a high risk of hemolysis, Dr. Ndour and his colleagues cautioned.
“Future large prospective studies will more precisely determine the robustness of prediction in different geographic and logistical settings,” the researchers wrote in their analysis.
The study was funded by the Bill & Melinda Gates Foundation, the French National Research Agency, and the Wellcome Trust. Five investigators, including Dr. Ndour, disclosed research grants from pharmaceutical firms for artesunate studies, two disclosed advisory board relationships with a Sigma Tau Laboratories, and another reported industry funding for anemia research related to artesunate.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: A positive result on an HRP2 test with diluted blood was 89% sensitive and 73% specific in predicting treatment-related anemia.
Data source: Two prospective cohorts of 95 artesunate-treated malaria patients in Bangladesh and 53 in France, plus a comparison cohort of 49 quinine-treated patients in France.
Disclosures: International foundations sponsored the study. Six of the investigators disclosed research support or other financial conflicts.
Daily 150-mg aspirin dose slashes preterm preeclampsia risk
While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.
New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).
After 156 women dropped out of the study or were lost to follow-up, investigators had results from 798 women in the aspirin group and 822 in the placebo group, with about 80% of subjects having taken aspirin or placebo as directed. The study’s primary outcome was delivery with preeclampsia before 37 weeks, seen in 13 women (1.6%) in the aspirin group, compared with 35 (4.3%) in the placebo group (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P = .004).
Other decisions incorporated into the study design, including those about aspirin dosage (higher than the currently recommended 60-80 mg for this population), taking aspirin at night, and the gestational age at which to start aspirin, were based on results from prior trials, studies, and meta-analyses, the researchers said.
Screening at 11-13 weeks’ gestation identifies less than 40% of term preeclampsia, studies have shown, and aspirin did not reduce term preeclampsia in this study, the investigators said.
The European Union Seventh Framework Program and the Fetal Medicine Foundation (UK) sponsored the study. None of the investigators had any relevant financial disclosures.
While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.
New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).
After 156 women dropped out of the study or were lost to follow-up, investigators had results from 798 women in the aspirin group and 822 in the placebo group, with about 80% of subjects having taken aspirin or placebo as directed. The study’s primary outcome was delivery with preeclampsia before 37 weeks, seen in 13 women (1.6%) in the aspirin group, compared with 35 (4.3%) in the placebo group (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P = .004).
Other decisions incorporated into the study design, including those about aspirin dosage (higher than the currently recommended 60-80 mg for this population), taking aspirin at night, and the gestational age at which to start aspirin, were based on results from prior trials, studies, and meta-analyses, the researchers said.
Screening at 11-13 weeks’ gestation identifies less than 40% of term preeclampsia, studies have shown, and aspirin did not reduce term preeclampsia in this study, the investigators said.
The European Union Seventh Framework Program and the Fetal Medicine Foundation (UK) sponsored the study. None of the investigators had any relevant financial disclosures.
While low-dose aspirin has been shown for decades to decrease the risk of preterm preeclampsia, yet to be established are the optimal dose and time of day to administer aspirin; how preeclampsia risk is best assessed; and at what gestational week it is best to start aspirin.
New findings from a randomized, double-blind, placebo-controlled trial show that a daily 150-mg dose of aspirin, taken at night, significantly reduced incidence of preterm preeclampsia in women identified as being at high risk in the first trimester (N Engl J Med. 2017 June 28. doi: 10.1056/NEJMoa1704559).
After 156 women dropped out of the study or were lost to follow-up, investigators had results from 798 women in the aspirin group and 822 in the placebo group, with about 80% of subjects having taken aspirin or placebo as directed. The study’s primary outcome was delivery with preeclampsia before 37 weeks, seen in 13 women (1.6%) in the aspirin group, compared with 35 (4.3%) in the placebo group (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P = .004).
Other decisions incorporated into the study design, including those about aspirin dosage (higher than the currently recommended 60-80 mg for this population), taking aspirin at night, and the gestational age at which to start aspirin, were based on results from prior trials, studies, and meta-analyses, the researchers said.
Screening at 11-13 weeks’ gestation identifies less than 40% of term preeclampsia, studies have shown, and aspirin did not reduce term preeclampsia in this study, the investigators said.
The European Union Seventh Framework Program and the Fetal Medicine Foundation (UK) sponsored the study. None of the investigators had any relevant financial disclosures.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Among patients taking aspirin, 1.6% developed preterm preeclampsia, compared with 4.3% of those taking placebo (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P = .004).
Data source: A randomized, international, multicenter trial enrolling nearly 1,800 women identified through screening as being at high risk of preeclampsia.
Disclosures: The European Union Seventh Framework Program and the Fetal Medicine Foundation (UK) sponsored the study. None of the investigators had any relevant financial disclosures.
VIDEO: Adding ultrasound to treat to target doesn’t improve RA remission outcomes
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Adding ultrasound to the treatment protocol actually reduced the likelihood of patients achieving remission by up to 66%, depending on the remission assessment used.
Data source: The observational study comprised 130 patients and more than 1,000 clinical visits.
Disclosures: Dr. Sepriano had no financial disclosures.
Pain often persists despite biologic treatment in PsA
MADRID – Pain is common in patients with psoriatic arthritis (PsA) and can be disruptive to their lives and jobs, even among those whose inflammatory symptoms have been treated with biologic drugs for 3 months or longer, according to findings from a multinational survey.
At the European Congress of Rheumatology, Dr. Philip G. Conaghan of the University of Leeds (England) presented findings from the survey of 782 consecutive PsA patients from 13 countries in Europe, the Middle East, Asia, and the Americas, as well as Australia. All patients included in the analysis were on biologic agents – mainly tumor necrosis factor inhibitors – for at least 90 days.
In an interview. Dr. Conaghan said that it’s important for clinicians not to assume that pain in a PsA patient on a biologic means that the drug is not working.
“The main limitation of our study is that we haven’t worked out how well-controlled patients’ psoriatic arthritis is, so, although we know they’re on a biologic for more than 3 months, we don’t know if they were responding well to it.” But, even in the absence of systemic inflammation, he said, there are other potential causes for pain that should not be overlooked.
“There’s no reason why PsA patients wouldn’t have pain due to tendinitis, enthesitis, and osteoarthritis – the same mechanical-type joint pain that we see in the whole community of people over 40,” Dr. Conaghan said. “I am concerned that, once we give someone a label of inflammatory arthritis, we stop looking at all the other things that can happen to their musculoskeletal system.”
Moreover, he said, “people who’ve had arthritis severe enough to need a biologic treatment will have muscle deconditioning and weakness. It’s very common that PsA patients have trouble opening jars and getting out of chairs.”
Such weakness “can lead to mechanical joint pain, which fortunately can be improved – along with the pain – through muscle strengthening and rehabilitation.”
For their study, Dr. Conaghan and his colleagues collected information from clinicians on treatment and from patients. The questionnaires incorporated several measures of disability, pain, functional impairment, and health-related quality of life that have been validated for use in PsA patients.
Severe pain was significantly associated with increased use of prescription nonsteroidal anti-inflammatory drugs and opioids, as well as nonprescription pain medication. Patients 65 years and older had a significantly greater likelihood of being unemployed or retired because of PsA if they reported severe pain, compared with those reporting mild or moderate pain.
A number of quality of life and work-related measures were also associated with pain severity. Dr. Conaghan and his colleagues found that the risk of disability increased with bodily pain, and more severe pain was associated with greater activity impairment, worse social functioning, more work impairment, and work time missed, among other measures (P less than .0001 for all).
“What we saw is that, the more pain you have, the more your world shrinks in,” Dr. Conaghan said.
Dr. Conaghan reported financial relationships with AbbVie, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Roche. Some of his study coauthors have similar disclosures. Four coauthors are employees of Novartis.
MADRID – Pain is common in patients with psoriatic arthritis (PsA) and can be disruptive to their lives and jobs, even among those whose inflammatory symptoms have been treated with biologic drugs for 3 months or longer, according to findings from a multinational survey.
At the European Congress of Rheumatology, Dr. Philip G. Conaghan of the University of Leeds (England) presented findings from the survey of 782 consecutive PsA patients from 13 countries in Europe, the Middle East, Asia, and the Americas, as well as Australia. All patients included in the analysis were on biologic agents – mainly tumor necrosis factor inhibitors – for at least 90 days.
In an interview. Dr. Conaghan said that it’s important for clinicians not to assume that pain in a PsA patient on a biologic means that the drug is not working.
“The main limitation of our study is that we haven’t worked out how well-controlled patients’ psoriatic arthritis is, so, although we know they’re on a biologic for more than 3 months, we don’t know if they were responding well to it.” But, even in the absence of systemic inflammation, he said, there are other potential causes for pain that should not be overlooked.
“There’s no reason why PsA patients wouldn’t have pain due to tendinitis, enthesitis, and osteoarthritis – the same mechanical-type joint pain that we see in the whole community of people over 40,” Dr. Conaghan said. “I am concerned that, once we give someone a label of inflammatory arthritis, we stop looking at all the other things that can happen to their musculoskeletal system.”
Moreover, he said, “people who’ve had arthritis severe enough to need a biologic treatment will have muscle deconditioning and weakness. It’s very common that PsA patients have trouble opening jars and getting out of chairs.”
Such weakness “can lead to mechanical joint pain, which fortunately can be improved – along with the pain – through muscle strengthening and rehabilitation.”
For their study, Dr. Conaghan and his colleagues collected information from clinicians on treatment and from patients. The questionnaires incorporated several measures of disability, pain, functional impairment, and health-related quality of life that have been validated for use in PsA patients.
Severe pain was significantly associated with increased use of prescription nonsteroidal anti-inflammatory drugs and opioids, as well as nonprescription pain medication. Patients 65 years and older had a significantly greater likelihood of being unemployed or retired because of PsA if they reported severe pain, compared with those reporting mild or moderate pain.
A number of quality of life and work-related measures were also associated with pain severity. Dr. Conaghan and his colleagues found that the risk of disability increased with bodily pain, and more severe pain was associated with greater activity impairment, worse social functioning, more work impairment, and work time missed, among other measures (P less than .0001 for all).
“What we saw is that, the more pain you have, the more your world shrinks in,” Dr. Conaghan said.
Dr. Conaghan reported financial relationships with AbbVie, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Roche. Some of his study coauthors have similar disclosures. Four coauthors are employees of Novartis.
MADRID – Pain is common in patients with psoriatic arthritis (PsA) and can be disruptive to their lives and jobs, even among those whose inflammatory symptoms have been treated with biologic drugs for 3 months or longer, according to findings from a multinational survey.
At the European Congress of Rheumatology, Dr. Philip G. Conaghan of the University of Leeds (England) presented findings from the survey of 782 consecutive PsA patients from 13 countries in Europe, the Middle East, Asia, and the Americas, as well as Australia. All patients included in the analysis were on biologic agents – mainly tumor necrosis factor inhibitors – for at least 90 days.
In an interview. Dr. Conaghan said that it’s important for clinicians not to assume that pain in a PsA patient on a biologic means that the drug is not working.
“The main limitation of our study is that we haven’t worked out how well-controlled patients’ psoriatic arthritis is, so, although we know they’re on a biologic for more than 3 months, we don’t know if they were responding well to it.” But, even in the absence of systemic inflammation, he said, there are other potential causes for pain that should not be overlooked.
“There’s no reason why PsA patients wouldn’t have pain due to tendinitis, enthesitis, and osteoarthritis – the same mechanical-type joint pain that we see in the whole community of people over 40,” Dr. Conaghan said. “I am concerned that, once we give someone a label of inflammatory arthritis, we stop looking at all the other things that can happen to their musculoskeletal system.”
Moreover, he said, “people who’ve had arthritis severe enough to need a biologic treatment will have muscle deconditioning and weakness. It’s very common that PsA patients have trouble opening jars and getting out of chairs.”
Such weakness “can lead to mechanical joint pain, which fortunately can be improved – along with the pain – through muscle strengthening and rehabilitation.”
For their study, Dr. Conaghan and his colleagues collected information from clinicians on treatment and from patients. The questionnaires incorporated several measures of disability, pain, functional impairment, and health-related quality of life that have been validated for use in PsA patients.
Severe pain was significantly associated with increased use of prescription nonsteroidal anti-inflammatory drugs and opioids, as well as nonprescription pain medication. Patients 65 years and older had a significantly greater likelihood of being unemployed or retired because of PsA if they reported severe pain, compared with those reporting mild or moderate pain.
A number of quality of life and work-related measures were also associated with pain severity. Dr. Conaghan and his colleagues found that the risk of disability increased with bodily pain, and more severe pain was associated with greater activity impairment, worse social functioning, more work impairment, and work time missed, among other measures (P less than .0001 for all).
“What we saw is that, the more pain you have, the more your world shrinks in,” Dr. Conaghan said.
Dr. Conaghan reported financial relationships with AbbVie, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Roche. Some of his study coauthors have similar disclosures. Four coauthors are employees of Novartis.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Overall, 37% of PsA patients reported severe pain despite treatment with biologic agents.
Data source: A multinational survey of 782 consecutive PsA patients on biologic agents.
Disclosures: Dr. Conaghan reported financial relationships with AbbVie, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Roche. Some of his study coauthors have similar disclosures. Four coauthors are employees of Novartis.
Studies provide insight into link between cancer immunotherapy and autoimmune disease
MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.
These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.
“This phenomenon was unknown to me and my group before [February 2016], when we started noting referrals of patients from oncology,” Dr. Calabrese said. “We were seeing symptoms of everything from Sjögren’s syndrome to inflammatory arthritis and myositis in patients being treated with these drugs for their cancer.” The same year, Dr. Calabrese and her team began coordinating an ongoing study to assess these patients.
Dr. Calabrese said that the cohort has shown so far that patients who develop autoimmune disease after immune checkpoint inhibitors “require much higher doses – of steroids in particular – to treat their symptoms,” and this can all too often result in being taken out of a clinical trial or having to stop cancer treatment.
Most of the patients in the cohort were treated with steroids only, while three patients received biologic agents, and four received methotrexate or antimalarials.
Dr. Calabrese said that the serology results were available for all the patients in the cohort and “were largely unremarkable.”
She noted that the rheumatic symptoms did not always resolve after pausing or stopping the cancer treatment. “We have some patients that have been off their checkpoint inhibitors for over a year and still have symptoms, so it’s looking like it might be a more long-term effect,” she said.
“In my unit, we also manage patients with myeloma, and I developed a weekly consultation with a cancer center,” Dr. Belkhir said. In 2015, she saw her first patient with RA and no previous history who had been treated with checkpoint inhibitors. That patient’s symptoms resolved after treatment with nonsteroidal anti-inflammatory drugs alone.
Dr. Belkhir is sharing results from this and five other patients presenting with symptoms of RA after their cancer treatment with immune checkpoint inhibitors, taken from a larger cohort of patients (n = 13) with a spectrum of rheumatic disease–like adverse effects. None of the six patients in this study had a previous clinical history of RA. They manifested their RA symptoms after a median of 1 month on cancer immunotherapy.
Some were able to continue their checkpoint inhibitors and be treated simultaneously for RA with steroids, antimalarials, methotrexate, and NSAIDs, Dr. Belkhir said. None received biologic agents, and each medication strategy, she said, was arrived at in consultation with the treating oncologist.
Dr. Belkhir’s team also looked closely at serology and found all six patients to be at least weakly, and mostly strongly, seropositive for RA. Three patients underwent testing for anticyclic citrullinated protein antibodies prior to starting cancer immunotherapy and two of these three were anti-CCP positive. Now, she said, the oncologists she’s working with are testing for anticyclic citrullinated peptides and rheumatoid factor prior to initiating cancer immunotherapy, so that this relationship is better understood.
“It is possible that antibodies were already present and that the anti-PD1 immunotherapy,” one type of immune checkpoint inhibitor, “acted as a trigger for the disease.” Animal studies have suggested a role for PD1 in the development of autoimmune disease, “but it’s not well investigated,” Dr. Belkhir said.
Dr. Belkhir and Dr. Calabrese both acknowledged that the understanding of checkpoint inhibitor–induced autoimmune disease is in its infancy. Clinical trials largely missed the phenomenon, the researchers said, because the trials were not designed to capture musculoskeletal adverse effects with the same granularity as other serious adverse events.
“This will be a long discussion in the months and the years ahead with oncologists,” Dr. Belkhir said.
Neither Dr. Calabrese nor Dr. Belkhir reported having any relevant conflicts of interest.
MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.
These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.
“This phenomenon was unknown to me and my group before [February 2016], when we started noting referrals of patients from oncology,” Dr. Calabrese said. “We were seeing symptoms of everything from Sjögren’s syndrome to inflammatory arthritis and myositis in patients being treated with these drugs for their cancer.” The same year, Dr. Calabrese and her team began coordinating an ongoing study to assess these patients.
Dr. Calabrese said that the cohort has shown so far that patients who develop autoimmune disease after immune checkpoint inhibitors “require much higher doses – of steroids in particular – to treat their symptoms,” and this can all too often result in being taken out of a clinical trial or having to stop cancer treatment.
Most of the patients in the cohort were treated with steroids only, while three patients received biologic agents, and four received methotrexate or antimalarials.
Dr. Calabrese said that the serology results were available for all the patients in the cohort and “were largely unremarkable.”
She noted that the rheumatic symptoms did not always resolve after pausing or stopping the cancer treatment. “We have some patients that have been off their checkpoint inhibitors for over a year and still have symptoms, so it’s looking like it might be a more long-term effect,” she said.
“In my unit, we also manage patients with myeloma, and I developed a weekly consultation with a cancer center,” Dr. Belkhir said. In 2015, she saw her first patient with RA and no previous history who had been treated with checkpoint inhibitors. That patient’s symptoms resolved after treatment with nonsteroidal anti-inflammatory drugs alone.
Dr. Belkhir is sharing results from this and five other patients presenting with symptoms of RA after their cancer treatment with immune checkpoint inhibitors, taken from a larger cohort of patients (n = 13) with a spectrum of rheumatic disease–like adverse effects. None of the six patients in this study had a previous clinical history of RA. They manifested their RA symptoms after a median of 1 month on cancer immunotherapy.
Some were able to continue their checkpoint inhibitors and be treated simultaneously for RA with steroids, antimalarials, methotrexate, and NSAIDs, Dr. Belkhir said. None received biologic agents, and each medication strategy, she said, was arrived at in consultation with the treating oncologist.
Dr. Belkhir’s team also looked closely at serology and found all six patients to be at least weakly, and mostly strongly, seropositive for RA. Three patients underwent testing for anticyclic citrullinated protein antibodies prior to starting cancer immunotherapy and two of these three were anti-CCP positive. Now, she said, the oncologists she’s working with are testing for anticyclic citrullinated peptides and rheumatoid factor prior to initiating cancer immunotherapy, so that this relationship is better understood.
“It is possible that antibodies were already present and that the anti-PD1 immunotherapy,” one type of immune checkpoint inhibitor, “acted as a trigger for the disease.” Animal studies have suggested a role for PD1 in the development of autoimmune disease, “but it’s not well investigated,” Dr. Belkhir said.
Dr. Belkhir and Dr. Calabrese both acknowledged that the understanding of checkpoint inhibitor–induced autoimmune disease is in its infancy. Clinical trials largely missed the phenomenon, the researchers said, because the trials were not designed to capture musculoskeletal adverse effects with the same granularity as other serious adverse events.
“This will be a long discussion in the months and the years ahead with oncologists,” Dr. Belkhir said.
Neither Dr. Calabrese nor Dr. Belkhir reported having any relevant conflicts of interest.
MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.
These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.
“This phenomenon was unknown to me and my group before [February 2016], when we started noting referrals of patients from oncology,” Dr. Calabrese said. “We were seeing symptoms of everything from Sjögren’s syndrome to inflammatory arthritis and myositis in patients being treated with these drugs for their cancer.” The same year, Dr. Calabrese and her team began coordinating an ongoing study to assess these patients.
Dr. Calabrese said that the cohort has shown so far that patients who develop autoimmune disease after immune checkpoint inhibitors “require much higher doses – of steroids in particular – to treat their symptoms,” and this can all too often result in being taken out of a clinical trial or having to stop cancer treatment.
Most of the patients in the cohort were treated with steroids only, while three patients received biologic agents, and four received methotrexate or antimalarials.
Dr. Calabrese said that the serology results were available for all the patients in the cohort and “were largely unremarkable.”
She noted that the rheumatic symptoms did not always resolve after pausing or stopping the cancer treatment. “We have some patients that have been off their checkpoint inhibitors for over a year and still have symptoms, so it’s looking like it might be a more long-term effect,” she said.
“In my unit, we also manage patients with myeloma, and I developed a weekly consultation with a cancer center,” Dr. Belkhir said. In 2015, she saw her first patient with RA and no previous history who had been treated with checkpoint inhibitors. That patient’s symptoms resolved after treatment with nonsteroidal anti-inflammatory drugs alone.
Dr. Belkhir is sharing results from this and five other patients presenting with symptoms of RA after their cancer treatment with immune checkpoint inhibitors, taken from a larger cohort of patients (n = 13) with a spectrum of rheumatic disease–like adverse effects. None of the six patients in this study had a previous clinical history of RA. They manifested their RA symptoms after a median of 1 month on cancer immunotherapy.
Some were able to continue their checkpoint inhibitors and be treated simultaneously for RA with steroids, antimalarials, methotrexate, and NSAIDs, Dr. Belkhir said. None received biologic agents, and each medication strategy, she said, was arrived at in consultation with the treating oncologist.
Dr. Belkhir’s team also looked closely at serology and found all six patients to be at least weakly, and mostly strongly, seropositive for RA. Three patients underwent testing for anticyclic citrullinated protein antibodies prior to starting cancer immunotherapy and two of these three were anti-CCP positive. Now, she said, the oncologists she’s working with are testing for anticyclic citrullinated peptides and rheumatoid factor prior to initiating cancer immunotherapy, so that this relationship is better understood.
“It is possible that antibodies were already present and that the anti-PD1 immunotherapy,” one type of immune checkpoint inhibitor, “acted as a trigger for the disease.” Animal studies have suggested a role for PD1 in the development of autoimmune disease, “but it’s not well investigated,” Dr. Belkhir said.
Dr. Belkhir and Dr. Calabrese both acknowledged that the understanding of checkpoint inhibitor–induced autoimmune disease is in its infancy. Clinical trials largely missed the phenomenon, the researchers said, because the trials were not designed to capture musculoskeletal adverse effects with the same granularity as other serious adverse events.
“This will be a long discussion in the months and the years ahead with oncologists,” Dr. Belkhir said.
Neither Dr. Calabrese nor Dr. Belkhir reported having any relevant conflicts of interest.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Rheumatic symptoms did not always resolve after pausing or stopping the cancer treatment, and some were able to continue their checkpoint inhibitors and be treated simultaneously for RA.
Data source: Two retrospective cohort reviews of patients on immune checkpoint inhibitors.
Disclosures: Neither Dr. Calabrese nor Dr. Belkhir reported having any relevant conflicts of interest.
Algorithm aims to tackle clozapine resistance
SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.
At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.
The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.
And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.
Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.
“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”
When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.
Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.
To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.
Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.
Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”
The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.
Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”
Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.
“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”
Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”
Dr. White disclosed no conflicts of interest related to his research.
SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.
At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.
The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.
And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.
Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.
“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”
When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.
Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.
To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.
Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.
Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”
The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.
Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”
Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.
“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”
Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”
Dr. White disclosed no conflicts of interest related to his research.
SAN DIEGO – The atypical antipsychotic drug clozapine is the standard of care for patients with treatment-resistant schizophrenia, but about half do not see an adequate response.
At the annual meeting of the American Psychiatric Association, Randall F. White, MD, presented an algorithm for clozapine-resistant patients intended to simplify and clarify a path forward. He also presented outcome data from a cohort of patients managed using this approach.
The algorithm recommends electroconvulsive therapy if there is inadequate response to clozapine alone or with fluvoxamine, which sometimes is used to boost clozapine serum level, especially in patients who are heavy smokers. If ECT fails to reduce symptoms or the patient refuses it, topiramate, aripiprazole, or sulpiride may be added to clozapine treatment, said Dr. White of the University of British Columbia, Vancouver.
And finally, if psychosis persists, certain patients should be offered cognitive-behavioral therapy with a psychologist trained in helping people with psychosis, Dr. White and his colleagues advise.
Dr. White said in an interview that the idea for a systematic approach to clozapine resistance came from clinical experience of the British Columbia Psychosis Program, which specializes in patients with severe schizophrenia and treatment resistance.
“About half of our patients come to us already on clozapine and aren’t getting better, so we needed to figure out a coherent approach to help them,” he said, noting that there is no current standard of care and that many “come to us already on four or five medications, and it can seem a bit random.”
When these patients are admitted, “we try to simplify their treatment and figure out what’s going on, and then offer ECT if appropriate,” he said.
Dr. White presented data from a cohort of patients assessed at the program between 2012 and 2017, of which 114 were taking clozapine at admission and had a diagnosis of schizophrenia or schizoaffective disorder.
To be considered clozapine-resistant, patients had to be taking 500 mg or more for at least 60 days, yet have persistent positive symptoms and moderate to severe impairment. Dr. White and his colleagues identified 20 patients with clozapine resistance. Of these, eight were offered ECT, and three accepted. At the time of discharge, 16 patients remained on clozapine with or without fluvoxamine. Four patients were treated with the recommended adjunctive agents aripiprazole or sulpiride and five with other agents.
Dr. White said the three agents recommended in the algorithm were determined by literature reviews, including meta-analyses of randomized trials. Several commonly used adjunctive agents to clozapine, including risperidone, were ruled out, for lack of evidence in this patient group.
Sulpiride, one of the drugs recommended in the algorithm, is not marketed in North America, and in Canada is accessible only by special arrangement. The evidence for aripiprazole, meanwhile, “is not stupendous,” Dr. White said, “but there’s a signal.”
The topiramate recommendation is based on results from a 2016 meta-analysis of randomized controlled trials. “Topiramate has a possible advantage of ameliorating metabolic problems,” Dr. White said, and the meta-analysis showed a significant effect size in improving positive and negative symptoms. However, he noted, on rare occasions, it has been seen to exacerbate psychosis.
Dr. White said few of the treatment-resistant patients seen in his program have had a course of ECT despite evidence of benefit. “Instead of ECT, they usually are put on multiple medications,” he said. “Admittedly, getting some of these patients to accept ECT isn’t easy.”
Because the program is designed to keep patients for 6 or more months as needed, “we have the luxury of time,” Dr. White said, to allow for the discontinuation of extraneous medicines and for an ECT trial if indicated.
“I know that in other hospitals, and other health care settings, they don’t have that – they have to figure out what to do quickly. And ECT is not the quickest treatment.”
Offering cognitive-behavioral therapy to people with psychosis is possible, he stressed, and supported by evidence from at least one study. “In this population, it’s challenging,” he acknowledged. “I don’t think I’d do it concurrently with ECT but as an alternative to or after ECT.”
Dr. White disclosed no conflicts of interest related to his research.
EXPERT ANALYSIS FROM APA
Impairment persists despite treatment in adult ADHD
SAN DIEGO – Despite treatment with short- or long-acting medications, adults with attention-deficit/hyperactivity disorder report more impairment than do non-ADHD adults across several domains of daily life, and at certain times of day.
The findings, from a study presented at the annual meeting of the American Psychiatric Association, suggest that adults with ADHD have burdens that may persist despite medication.
The studies compared a cohort of 616 adults with a self-reported ADHD diagnosis and at least 6 months on medication, including short-acting stimulants, long-acting agents, or a combination of these. The researchers also recruited a comparison cohort of 200 non-ADHD adults.
“Interestingly, there was not only a difference between ADHD and non-ADHD groups, but there was also significant impairment reported among patients who are currently being treated for ADHD,” Alexandra Khachatryan, MPH, of Shire Pharmaceuticals, the study’s senior author, said in an interview. Ms. Khachatryan and her colleagues presented the findings at the APA.
For example, 44% of the ADHD respondents reported that the afternoon was the most challenging time of day, compared with 29% of non-ADHD participants (P less than .001). Mid-morning also was significantly more challenging for the ADHD group, with 26% reporting difficulties, compared with 17% of the non-ADHD cohort (P less than .01).
Other statistically significant between-group differences were seen related to managing affect and emotions, sustaining effort, working memory and recall, and interpersonal relationships.
“In addition to the burden patients report across the day, they also expressed significant challenges with psychosocial functioning and managing the demands of work, social, and family life despite treatment,” said Norman Atkins, PhD, of Shire, a coauthor of the study.
A separate poster by the same research group, using the same study data from the cohort of 616 currently treated adult ADHD patients (mean age 39, 70% female) looked at self-reported impairment across daily life domains by patients under different medication regimens.
Patients in the cohort were treated with short-acting stimulants (n = 166), long-acting stimulants (n = 201), or augmentation strategies (n = 249). The researchers found that afternoons and evenings were most difficult for patients regardless of treatment approach.
Ms. Khachatryan said the study was intended to help clinicians “understand what we’re offering patients and if we’re adequately meeting the needs of patients across the day. And we found that adults experience burden across the day despite being treated, and what they report as the most challenging times of day are the afternoon and evening hours,” when work, family, and household obligations are likely to be present.
Dr. Atkins added: “From an ADHD management perspective, the key takeaway is that these impairments occur across multiple settings and are most problematic at certain times of the day. It’s important for providers to have a meaningful conversation with their patients about their day-to-day challenges to fully appreciate how ADHD impacts their functioning so they can best optimize care.”
The researchers acknowledged as limitations of their study its high number of women participants, potentially reducing the generalizability of its findings; the reliance on self-reported outcomes; and between-group differences for the ADHD and non-ADHD groups that included differences in mean age (39 vs. 43, respectively) and full-time employment status (57% vs. 42%).
The study was sponsored by Shire Pharmaceuticals, with three of its five coauthors employed by the company.
SAN DIEGO – Despite treatment with short- or long-acting medications, adults with attention-deficit/hyperactivity disorder report more impairment than do non-ADHD adults across several domains of daily life, and at certain times of day.
The findings, from a study presented at the annual meeting of the American Psychiatric Association, suggest that adults with ADHD have burdens that may persist despite medication.
The studies compared a cohort of 616 adults with a self-reported ADHD diagnosis and at least 6 months on medication, including short-acting stimulants, long-acting agents, or a combination of these. The researchers also recruited a comparison cohort of 200 non-ADHD adults.
“Interestingly, there was not only a difference between ADHD and non-ADHD groups, but there was also significant impairment reported among patients who are currently being treated for ADHD,” Alexandra Khachatryan, MPH, of Shire Pharmaceuticals, the study’s senior author, said in an interview. Ms. Khachatryan and her colleagues presented the findings at the APA.
For example, 44% of the ADHD respondents reported that the afternoon was the most challenging time of day, compared with 29% of non-ADHD participants (P less than .001). Mid-morning also was significantly more challenging for the ADHD group, with 26% reporting difficulties, compared with 17% of the non-ADHD cohort (P less than .01).
Other statistically significant between-group differences were seen related to managing affect and emotions, sustaining effort, working memory and recall, and interpersonal relationships.
“In addition to the burden patients report across the day, they also expressed significant challenges with psychosocial functioning and managing the demands of work, social, and family life despite treatment,” said Norman Atkins, PhD, of Shire, a coauthor of the study.
A separate poster by the same research group, using the same study data from the cohort of 616 currently treated adult ADHD patients (mean age 39, 70% female) looked at self-reported impairment across daily life domains by patients under different medication regimens.
Patients in the cohort were treated with short-acting stimulants (n = 166), long-acting stimulants (n = 201), or augmentation strategies (n = 249). The researchers found that afternoons and evenings were most difficult for patients regardless of treatment approach.
Ms. Khachatryan said the study was intended to help clinicians “understand what we’re offering patients and if we’re adequately meeting the needs of patients across the day. And we found that adults experience burden across the day despite being treated, and what they report as the most challenging times of day are the afternoon and evening hours,” when work, family, and household obligations are likely to be present.
Dr. Atkins added: “From an ADHD management perspective, the key takeaway is that these impairments occur across multiple settings and are most problematic at certain times of the day. It’s important for providers to have a meaningful conversation with their patients about their day-to-day challenges to fully appreciate how ADHD impacts their functioning so they can best optimize care.”
The researchers acknowledged as limitations of their study its high number of women participants, potentially reducing the generalizability of its findings; the reliance on self-reported outcomes; and between-group differences for the ADHD and non-ADHD groups that included differences in mean age (39 vs. 43, respectively) and full-time employment status (57% vs. 42%).
The study was sponsored by Shire Pharmaceuticals, with three of its five coauthors employed by the company.
SAN DIEGO – Despite treatment with short- or long-acting medications, adults with attention-deficit/hyperactivity disorder report more impairment than do non-ADHD adults across several domains of daily life, and at certain times of day.
The findings, from a study presented at the annual meeting of the American Psychiatric Association, suggest that adults with ADHD have burdens that may persist despite medication.
The studies compared a cohort of 616 adults with a self-reported ADHD diagnosis and at least 6 months on medication, including short-acting stimulants, long-acting agents, or a combination of these. The researchers also recruited a comparison cohort of 200 non-ADHD adults.
“Interestingly, there was not only a difference between ADHD and non-ADHD groups, but there was also significant impairment reported among patients who are currently being treated for ADHD,” Alexandra Khachatryan, MPH, of Shire Pharmaceuticals, the study’s senior author, said in an interview. Ms. Khachatryan and her colleagues presented the findings at the APA.
For example, 44% of the ADHD respondents reported that the afternoon was the most challenging time of day, compared with 29% of non-ADHD participants (P less than .001). Mid-morning also was significantly more challenging for the ADHD group, with 26% reporting difficulties, compared with 17% of the non-ADHD cohort (P less than .01).
Other statistically significant between-group differences were seen related to managing affect and emotions, sustaining effort, working memory and recall, and interpersonal relationships.
“In addition to the burden patients report across the day, they also expressed significant challenges with psychosocial functioning and managing the demands of work, social, and family life despite treatment,” said Norman Atkins, PhD, of Shire, a coauthor of the study.
A separate poster by the same research group, using the same study data from the cohort of 616 currently treated adult ADHD patients (mean age 39, 70% female) looked at self-reported impairment across daily life domains by patients under different medication regimens.
Patients in the cohort were treated with short-acting stimulants (n = 166), long-acting stimulants (n = 201), or augmentation strategies (n = 249). The researchers found that afternoons and evenings were most difficult for patients regardless of treatment approach.
Ms. Khachatryan said the study was intended to help clinicians “understand what we’re offering patients and if we’re adequately meeting the needs of patients across the day. And we found that adults experience burden across the day despite being treated, and what they report as the most challenging times of day are the afternoon and evening hours,” when work, family, and household obligations are likely to be present.
Dr. Atkins added: “From an ADHD management perspective, the key takeaway is that these impairments occur across multiple settings and are most problematic at certain times of the day. It’s important for providers to have a meaningful conversation with their patients about their day-to-day challenges to fully appreciate how ADHD impacts their functioning so they can best optimize care.”
The researchers acknowledged as limitations of their study its high number of women participants, potentially reducing the generalizability of its findings; the reliance on self-reported outcomes; and between-group differences for the ADHD and non-ADHD groups that included differences in mean age (39 vs. 43, respectively) and full-time employment status (57% vs. 42%).
The study was sponsored by Shire Pharmaceuticals, with three of its five coauthors employed by the company.
AT APA