Amy Karon

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Changes in the sequence of RNA – also known as RNA editing – might contribute to the pathogenesis and prognosis of gastric cancer, investigators reported in the October issue of Gastroenterology.

By performing high-throughput transcriptome sequencing (or RNA-Seq) of gastric tumor tissue and cell lines, they identified “a clear RNA misediting phenotype” characterized by an imbalance in enzymes called adenosine deaminases that act on RNA, or ADAR, Tim Hon Man Chan, MD, of the National University of Singapore and his associates said. Normal gastric tissue did not show these changes, and they were associated with tumor progression and a poor prognosis, the investigators added.

Gastric cancer is the third most lethal malignancy worldwide. RNA editing in humans usually involves the conversion of adenosine-to-inosine (A-to-I), which is catalyzed by the ADAR1 and ADAR2 enzymes and has been linked to liver and esophageal cancer. To explore the role of A-to-I RNA editing in gastric cancer, the researchers performed next-generation sequencing transcriptomics of 14 tissue specimens from primary gastric tumors and 14 matched samples from noncancerous gastric tissue. They also sequenced gastric cancer cell lines and analyzed single nucleotide polymorphism array and RNA-Seq data from the gastric cancer datasets of The Cancer Genome Atlas (Gastroenterology. 2016 Jun 30. doi: 10.1053/j.gastro.2016.06.043). 

Compared with normal tissue specimens, almost all the samples of gastric cancers showed clear evidence of ADAR dysregulation – specifically, the gain of the ADAR1 gene and the loss of the ADAR2 gene, the researchers said. Furthermore, both the in vivo and in vitro studies indicated that RNA editing enabled ADAR1 to function as an oncogene in gastric cancer, while ADAR2 functioned as a tumor suppressor gene. In The Cancer Genome Atlas, about 36% of gastric cancer patients had gained ADAR1, while 44% of patients had lost ADAR2. Not only did these changes lead to a significant rise in ADAR1 mRNA expression and a significant decrease in ADAR2 mRNA expression, but patients with the most developed gastric tumors had the highest levels of ADAR1/ADAR2 dysregulation and the worst clinical prognosis, the investigators said.

SOURCE: American Gastroenterological Association

Additional tests of a model target gene called PODXL (podocalyxin-like) showed that ADAR2 regulates the editing of codon 241 such that histidine is replaced with arginine, which then neutralizes the normal tumorigenic ability of unedited or wild-type PODXL, the researchers reported. “Our data suggest that dysregulation of RNA editing is pervasive in gastric cancer, approaching levels reported for other types of epigenetic dysregulation including DNA methylation and histone modification,” they added. Taken together, the findings “highlight RNA editing as an important pathogenic mechanism in gastric carcinogenesis, and ADAR enzymes as potential gastric cancer therapeutic targets.” 

These findings are especially important because the identification of DNA mutations in gastric cancer has not led to viable therapies except for traztuzumab in ERBB2-positive gastric cancer and ramucirumab in advanced gastric cancer, the investigators said. “Our study demonstrates that differentially expressed ADARs in gastric tumors with consequent A-to-I RNA editing dysregulation may serve as a second layer of ‘somatic mutations’ and a novel contributor to gastric cancer,” they concluded.

The work was funded by the National Research Foundation Singapore, the Singapore Ministry of Education, and several other noncorporate entities. The researchers had no disclosures.
 

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Treating inflammatory bowel disease with biologic therapies increases the risk of opportunistic infections but not the risk of serious infections, based on a systematic review and meta-analysis reported in the October issue of Clinical Gastroenterology and Hepatology.

Contrary to common belief, infection risk seemed similar with the integrin and anti–tumor necrosis factor classes, said Stefanos Bonovas, MD, MSc, PhD, of Humanitas Clinical and Research Center, Milan, with his associates. Clinicians and patients can use these findings to better weigh the risks and benefits of biologic therapies for IBD, although “studies in real-world settings, national and international registries, and clinical audits may serve as complementary data sources to further assess biologic treatments’ comparative and long-term safety profiles,” the researchers added.

Biologics can effectively manage IBD but raise concerns about infection and malignancy. To examine these risks in adults with IBD, the researchers systematically searched PubMed, Embase, Scopus, the Cochrane IBD Group Specialized Trials Register, the World Health Organization International Clinical Trials Registry Platform, and clinicaltrials.gov through March 2016 for randomized, placebo-controlled or head-to-head trials of approved IBD therapies, including adalimumab, certolizumab, golimumab, infliximab, natalizumab, and vedolizumab. After excluding systematic reviews, uncontrolled trials, and secondary analyses, 49 trials of 14,590 patients remained for meta-analysis, the investigators said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.039).

Biologic therapy conferred a “moderate increase” in the likelihood of any infection, with an odds ratio of 1.19 when compared with patients who did not receive biologics (95% confidence interval, 1.10-1.29), the researchers said. The risk of opportunistic infections was somewhat higher (OR, 1.90; 95% CI, 1.21-3.01). However, biologic therapy did not significantly heighten the risk of serious infections, which most studies defined as infections leading to hospitalization, intravenous antibiotic treatment, or death (OR, 0.89; 95% CI, 0.71-1.12). “On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90),” the investigators wrote. They did not find an increased risk of malignancy with biologic therapy (OR, 0.90; 95% CI, 0.54-1.50), “but [these] data were insufficient in terms of exposure and follow-up times,” they added.

Comparisons of individual agents and classes also did not reveal any significant associations with the risk of infection, the investigators noted. They did acknowledge several limitations. None of the trials were head-to-head comparisons between biologics, and many were industry funded. Estimates of comparative harm were based on indirect comparisons, and therefore merited cautious interpretation. Because the trials were carried out for regulatory purposes, they enrolled highly selected and homogeneous cohorts of IBD patients, leading to underrepresentation of high-risk and elderly individuals, the researchers noted. “Finally, the exposure and follow-up times were up to 24 months, a time period that is considered sufficient when analyzing infectious adverse effects but wholly insufficient for cancer outcomes. With this in mind, we must look to large register-based cohort studies to enhance our understanding of the biologics-cancer association, despite the biases inherent in observational study designs.”

Dr. Bonovas had no disclosures, while three coauthors reported relationships with a number of pharmaceutical companies.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized clinical trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

Intravenous ceftazidime-avibactam successfully treated 59% of carbapenem-resistant Enterobacteriaceae (CRE) infections, and 76% of patients remained alive at 30 days, according to a retrospective cohort study published in Clinical Infectious Diseases.

Those rates resemble previous reports of treatment with in vitro active agents, while the rate of acute kidney injury was about a third lower, said Ryan K. Shields, PharmD, of the University of Pittsburgh, and his associates. But 8% of CRE infections developed ceftazidime-avibactam resistance, which accounted for about a third of microbiological failures, the researchers said. “It is incumbent upon health care providers to share their clinical experiences with ceftazidime-avibactam and other new beta-lactamase inhibitors, so these agents can be used most effectively for the longest period of time,” they added.

James Gathany/CDC

Ceftazidime-avibactam (Avycaz) is a novel beta-lactam/beta-lactamase inhibitor combination approved by the Food and Drug Administration in 2015 for complicated intra-abdominal and urinary tract infections. It was hoped that the newly approved combination would prove safer and more effective than previously developed agents that showed in vitro activity against CRE, such as colistin, gentamicin, and tigecycline, the researchers noted.

They described CRE-infected patients treated with ceftazidime-avibactam (median, 14 days; range, 4-71 days) between April 2015 and February 2016. The average age of the patients was 64 years (range 26-78 years), and 57% were men. Infections included ventilator or health care–associated pneumonia, primary bacteremia, intra-abdominal infection, skin and soft tissue infections, pyelonephritis, mediastinitis, subdural empyema/ventriculitis, and purulent tracheobronchitis. All the CRE isolates were susceptible to ceftazidime-avibactam at baseline. In all, 70% of patients received ceftazidime-avibactam as monotherapy, while 30% received it in combination with intravenous or inhaled gentamicin, intravenous or intrathecal colistin, or tigecycline (Clin Infect Dis. 2016 Sep 13. doi: 10.1093/cid/ciw636).

A total of 28 (76%) patients were alive at 30 days and 62% were alive at 90 days, the investigators said. They calculated a 59% rate of clinical success, defined as absence of recurrence within 30 days of onset, resolution of signs and symptoms, and sterilization of site-specific cultures within 7 days of treatment. Combination therapy did not improve the chances of clinical success, they noted. Among the 15 clinical failures, 9 patients died, 4 developed recurrent CRE infections, and 2 did not clinically improve. Clinical success was less likely when patients needed continuous renal replacement therapy (17% vs. 68% for other patients; P = .03) or had higher Sequential Organ Failure Assessment (SOFA) scores (average, 5.2 in clinical successes vs. 8.8 in clinical failures; P = .047). In addition, 10% of patients developed acute kidney injury within 7 days of starting treatment, which was “considerably lower than the approximately 30% rate we previously reported with carbapenem-colistin or aminoglycoside-based combinations,” the investigators said.

The sample size was too small to definitively answer questions about whether combination regimens can overcome resistance, improve outcomes, or effectively treat specific types of CRE infection, the researchers noted. “Nevertheless, we can conclude that ceftazidime-avibactam offers an important advance in the treatment of CRE infections,” they wrote. “The development of resistance after as few as 10 days of therapy is troubling, and treatment failures and deaths in a significant minority of patients highlight the need for more agents with activity against CRE.”

The University of Pittsburgh Medical Center and the National Institutes of Health provided funding. One coauthor disclosed ties to Meiji, Shionogi, Tetraphase, Achaogen, Merck, and The Medicines Company. The other authors had no disclosures.

Intravenous ceftazidime-avibactam successfully treated 59% of carbapenem-resistant Enterobacteriaceae (CRE) infections, and 76% of patients remained alive at 30 days, according to a retrospective cohort study published in Clinical Infectious Diseases.

Those rates resemble previous reports of treatment with in vitro active agents, while the rate of acute kidney injury was about a third lower, said Ryan K. Shields, PharmD, of the University of Pittsburgh, and his associates. But 8% of CRE infections developed ceftazidime-avibactam resistance, which accounted for about a third of microbiological failures, the researchers said. “It is incumbent upon health care providers to share their clinical experiences with ceftazidime-avibactam and other new beta-lactamase inhibitors, so these agents can be used most effectively for the longest period of time,” they added.

James Gathany/CDC

Ceftazidime-avibactam (Avycaz) is a novel beta-lactam/beta-lactamase inhibitor combination approved by the Food and Drug Administration in 2015 for complicated intra-abdominal and urinary tract infections. It was hoped that the newly approved combination would prove safer and more effective than previously developed agents that showed in vitro activity against CRE, such as colistin, gentamicin, and tigecycline, the researchers noted.

They described CRE-infected patients treated with ceftazidime-avibactam (median, 14 days; range, 4-71 days) between April 2015 and February 2016. The average age of the patients was 64 years (range 26-78 years), and 57% were men. Infections included ventilator or health care–associated pneumonia, primary bacteremia, intra-abdominal infection, skin and soft tissue infections, pyelonephritis, mediastinitis, subdural empyema/ventriculitis, and purulent tracheobronchitis. All the CRE isolates were susceptible to ceftazidime-avibactam at baseline. In all, 70% of patients received ceftazidime-avibactam as monotherapy, while 30% received it in combination with intravenous or inhaled gentamicin, intravenous or intrathecal colistin, or tigecycline (Clin Infect Dis. 2016 Sep 13. doi: 10.1093/cid/ciw636).

A total of 28 (76%) patients were alive at 30 days and 62% were alive at 90 days, the investigators said. They calculated a 59% rate of clinical success, defined as absence of recurrence within 30 days of onset, resolution of signs and symptoms, and sterilization of site-specific cultures within 7 days of treatment. Combination therapy did not improve the chances of clinical success, they noted. Among the 15 clinical failures, 9 patients died, 4 developed recurrent CRE infections, and 2 did not clinically improve. Clinical success was less likely when patients needed continuous renal replacement therapy (17% vs. 68% for other patients; P = .03) or had higher Sequential Organ Failure Assessment (SOFA) scores (average, 5.2 in clinical successes vs. 8.8 in clinical failures; P = .047). In addition, 10% of patients developed acute kidney injury within 7 days of starting treatment, which was “considerably lower than the approximately 30% rate we previously reported with carbapenem-colistin or aminoglycoside-based combinations,” the investigators said.

The sample size was too small to definitively answer questions about whether combination regimens can overcome resistance, improve outcomes, or effectively treat specific types of CRE infection, the researchers noted. “Nevertheless, we can conclude that ceftazidime-avibactam offers an important advance in the treatment of CRE infections,” they wrote. “The development of resistance after as few as 10 days of therapy is troubling, and treatment failures and deaths in a significant minority of patients highlight the need for more agents with activity against CRE.”

The University of Pittsburgh Medical Center and the National Institutes of Health provided funding. One coauthor disclosed ties to Meiji, Shionogi, Tetraphase, Achaogen, Merck, and The Medicines Company. The other authors had no disclosures.

Intravenous ceftazidime-avibactam successfully treated 59% of carbapenem-resistant Enterobacteriaceae (CRE) infections, and 76% of patients remained alive at 30 days, according to a retrospective cohort study published in Clinical Infectious Diseases.

Those rates resemble previous reports of treatment with in vitro active agents, while the rate of acute kidney injury was about a third lower, said Ryan K. Shields, PharmD, of the University of Pittsburgh, and his associates. But 8% of CRE infections developed ceftazidime-avibactam resistance, which accounted for about a third of microbiological failures, the researchers said. “It is incumbent upon health care providers to share their clinical experiences with ceftazidime-avibactam and other new beta-lactamase inhibitors, so these agents can be used most effectively for the longest period of time,” they added.

James Gathany/CDC

Ceftazidime-avibactam (Avycaz) is a novel beta-lactam/beta-lactamase inhibitor combination approved by the Food and Drug Administration in 2015 for complicated intra-abdominal and urinary tract infections. It was hoped that the newly approved combination would prove safer and more effective than previously developed agents that showed in vitro activity against CRE, such as colistin, gentamicin, and tigecycline, the researchers noted.

They described CRE-infected patients treated with ceftazidime-avibactam (median, 14 days; range, 4-71 days) between April 2015 and February 2016. The average age of the patients was 64 years (range 26-78 years), and 57% were men. Infections included ventilator or health care–associated pneumonia, primary bacteremia, intra-abdominal infection, skin and soft tissue infections, pyelonephritis, mediastinitis, subdural empyema/ventriculitis, and purulent tracheobronchitis. All the CRE isolates were susceptible to ceftazidime-avibactam at baseline. In all, 70% of patients received ceftazidime-avibactam as monotherapy, while 30% received it in combination with intravenous or inhaled gentamicin, intravenous or intrathecal colistin, or tigecycline (Clin Infect Dis. 2016 Sep 13. doi: 10.1093/cid/ciw636).

A total of 28 (76%) patients were alive at 30 days and 62% were alive at 90 days, the investigators said. They calculated a 59% rate of clinical success, defined as absence of recurrence within 30 days of onset, resolution of signs and symptoms, and sterilization of site-specific cultures within 7 days of treatment. Combination therapy did not improve the chances of clinical success, they noted. Among the 15 clinical failures, 9 patients died, 4 developed recurrent CRE infections, and 2 did not clinically improve. Clinical success was less likely when patients needed continuous renal replacement therapy (17% vs. 68% for other patients; P = .03) or had higher Sequential Organ Failure Assessment (SOFA) scores (average, 5.2 in clinical successes vs. 8.8 in clinical failures; P = .047). In addition, 10% of patients developed acute kidney injury within 7 days of starting treatment, which was “considerably lower than the approximately 30% rate we previously reported with carbapenem-colistin or aminoglycoside-based combinations,” the investigators said.

The sample size was too small to definitively answer questions about whether combination regimens can overcome resistance, improve outcomes, or effectively treat specific types of CRE infection, the researchers noted. “Nevertheless, we can conclude that ceftazidime-avibactam offers an important advance in the treatment of CRE infections,” they wrote. “The development of resistance after as few as 10 days of therapy is troubling, and treatment failures and deaths in a significant minority of patients highlight the need for more agents with activity against CRE.”

The University of Pittsburgh Medical Center and the National Institutes of Health provided funding. One coauthor disclosed ties to Meiji, Shionogi, Tetraphase, Achaogen, Merck, and The Medicines Company. The other authors had no disclosures.

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.

Nearly half of patients were readmitted to the hospital within 90 days of liver transplantation, according to a single-center retrospective study.

“As readmission portends decreased survival, an emphasis should be placed on identifying and optimizing those at increased risk. If readmission does occur, however, it presents an opportunity to intervene, as virtually no patients died during initial readmission,” Madhukar S. Patel, MD, and his associates at Massachusetts General Hospital, Boston, wrote online in HPB.

©Wavebreakmedia Ltd/ThinkStockPhotos.com

Long wait times for liver transplantation in this part of the country lead to “high patient acuity,” the researchers noted. To better understand the correlates and consequences of posttransplant readmissions, they reviewed the records for 325 adults who underwent liver transplantation at their hospital between 2005 and 2015. Patients averaged 56 years old and had awaited transplant for a mean of 1 year (standard deviation, 506 days). Their average MELD (Model for End-Stage Liver Disease) scores were 30.3 at transplant (SD, 5.8), and 16.9 (SD, 9.4) on postoperative day 5. Their average hospital length of stay was 12 days, the investigators reported (HPB. 2016 Sep 15. doi: 10.1016/j.hpb.2016.08.003). A total of 149 patients (46%) were readmitted within 90 days of discharge, most often for infections (28% of readmissions), followed by medication issues (19%) and biliary complications (11%). The strongest predictor of posttransplant readmission was hepatitis C virus (HCV) infection, which more than doubled the odds of readmission, compared with alcoholic liver disease (odds ratio, 2.37; 95% confidence interval, 1.44-3.91; P = .001). Transplantees with HCV might benefit from closer outpatient follow-up to detect worsening liver function, diagnostic algorithms to help prevent unnecessary readmissions, and associated nosocomial infections, and pre- and posttransplant direct-acting antiviral therapy, “although the impact [of direct-acting antiviral] therapy on readmissions] is unknown at this time,” the investigators said.

The multivariable analysis also linked readmissions to longer hospital stays (OR, 1.03; P = .04), while age and male sex were protective factors, the investigators said. “Although speculative, it is possible that these factors may be protective due to differences in social support structures upon discharge,” they wrote, noting that women are more likely than men to outlive their partners and thus to live alone in later life.

Readmission within 90 days was associated with a significantly lower rate of survival at 5 years (75% vs. 88% for patients who were not readmitted; P = .008). But only one patient died during the initial readmission, “suggesting that when readmission does occur, it may be an opportunity to intervene,” the researchers said. Strategies include earlier extubation and removal of indwelling catheters, decreasing levels of immunosuppression, lowering treatment thresholds, and shifting patients with laboratory abnormalities to the outpatient setting, they noted. “At our center a process has been initiated in which the inpatient transplant attending surgeon directly passes off discharged patients to the outpatient team,” the investigators wrote. “Additionally, for patients discharged to an acute rehabilitation facility, a specific transplant physician point of contact is provided to the team at the rehab center in case any questions or issues arise [after] discharge. Although these strategies are a reasonable starting point, follow-up studies remain necessary in order to evaluate the impact of these interventions in this patient cohort.”

The researchers reported no funding sources and had no relevant financial disclosures.

Nearly half of patients were readmitted to the hospital within 90 days of liver transplantation, according to a single-center retrospective study.

“As readmission portends decreased survival, an emphasis should be placed on identifying and optimizing those at increased risk. If readmission does occur, however, it presents an opportunity to intervene, as virtually no patients died during initial readmission,” Madhukar S. Patel, MD, and his associates at Massachusetts General Hospital, Boston, wrote online in HPB.

©Wavebreakmedia Ltd/ThinkStockPhotos.com

Long wait times for liver transplantation in this part of the country lead to “high patient acuity,” the researchers noted. To better understand the correlates and consequences of posttransplant readmissions, they reviewed the records for 325 adults who underwent liver transplantation at their hospital between 2005 and 2015. Patients averaged 56 years old and had awaited transplant for a mean of 1 year (standard deviation, 506 days). Their average MELD (Model for End-Stage Liver Disease) scores were 30.3 at transplant (SD, 5.8), and 16.9 (SD, 9.4) on postoperative day 5. Their average hospital length of stay was 12 days, the investigators reported (HPB. 2016 Sep 15. doi: 10.1016/j.hpb.2016.08.003). A total of 149 patients (46%) were readmitted within 90 days of discharge, most often for infections (28% of readmissions), followed by medication issues (19%) and biliary complications (11%). The strongest predictor of posttransplant readmission was hepatitis C virus (HCV) infection, which more than doubled the odds of readmission, compared with alcoholic liver disease (odds ratio, 2.37; 95% confidence interval, 1.44-3.91; P = .001). Transplantees with HCV might benefit from closer outpatient follow-up to detect worsening liver function, diagnostic algorithms to help prevent unnecessary readmissions, and associated nosocomial infections, and pre- and posttransplant direct-acting antiviral therapy, “although the impact [of direct-acting antiviral] therapy on readmissions] is unknown at this time,” the investigators said.

The multivariable analysis also linked readmissions to longer hospital stays (OR, 1.03; P = .04), while age and male sex were protective factors, the investigators said. “Although speculative, it is possible that these factors may be protective due to differences in social support structures upon discharge,” they wrote, noting that women are more likely than men to outlive their partners and thus to live alone in later life.

Readmission within 90 days was associated with a significantly lower rate of survival at 5 years (75% vs. 88% for patients who were not readmitted; P = .008). But only one patient died during the initial readmission, “suggesting that when readmission does occur, it may be an opportunity to intervene,” the researchers said. Strategies include earlier extubation and removal of indwelling catheters, decreasing levels of immunosuppression, lowering treatment thresholds, and shifting patients with laboratory abnormalities to the outpatient setting, they noted. “At our center a process has been initiated in which the inpatient transplant attending surgeon directly passes off discharged patients to the outpatient team,” the investigators wrote. “Additionally, for patients discharged to an acute rehabilitation facility, a specific transplant physician point of contact is provided to the team at the rehab center in case any questions or issues arise [after] discharge. Although these strategies are a reasonable starting point, follow-up studies remain necessary in order to evaluate the impact of these interventions in this patient cohort.”

The researchers reported no funding sources and had no relevant financial disclosures.

Nearly half of patients were readmitted to the hospital within 90 days of liver transplantation, according to a single-center retrospective study.

“As readmission portends decreased survival, an emphasis should be placed on identifying and optimizing those at increased risk. If readmission does occur, however, it presents an opportunity to intervene, as virtually no patients died during initial readmission,” Madhukar S. Patel, MD, and his associates at Massachusetts General Hospital, Boston, wrote online in HPB.

©Wavebreakmedia Ltd/ThinkStockPhotos.com

Long wait times for liver transplantation in this part of the country lead to “high patient acuity,” the researchers noted. To better understand the correlates and consequences of posttransplant readmissions, they reviewed the records for 325 adults who underwent liver transplantation at their hospital between 2005 and 2015. Patients averaged 56 years old and had awaited transplant for a mean of 1 year (standard deviation, 506 days). Their average MELD (Model for End-Stage Liver Disease) scores were 30.3 at transplant (SD, 5.8), and 16.9 (SD, 9.4) on postoperative day 5. Their average hospital length of stay was 12 days, the investigators reported (HPB. 2016 Sep 15. doi: 10.1016/j.hpb.2016.08.003). A total of 149 patients (46%) were readmitted within 90 days of discharge, most often for infections (28% of readmissions), followed by medication issues (19%) and biliary complications (11%). The strongest predictor of posttransplant readmission was hepatitis C virus (HCV) infection, which more than doubled the odds of readmission, compared with alcoholic liver disease (odds ratio, 2.37; 95% confidence interval, 1.44-3.91; P = .001). Transplantees with HCV might benefit from closer outpatient follow-up to detect worsening liver function, diagnostic algorithms to help prevent unnecessary readmissions, and associated nosocomial infections, and pre- and posttransplant direct-acting antiviral therapy, “although the impact [of direct-acting antiviral] therapy on readmissions] is unknown at this time,” the investigators said.

The multivariable analysis also linked readmissions to longer hospital stays (OR, 1.03; P = .04), while age and male sex were protective factors, the investigators said. “Although speculative, it is possible that these factors may be protective due to differences in social support structures upon discharge,” they wrote, noting that women are more likely than men to outlive their partners and thus to live alone in later life.

Readmission within 90 days was associated with a significantly lower rate of survival at 5 years (75% vs. 88% for patients who were not readmitted; P = .008). But only one patient died during the initial readmission, “suggesting that when readmission does occur, it may be an opportunity to intervene,” the researchers said. Strategies include earlier extubation and removal of indwelling catheters, decreasing levels of immunosuppression, lowering treatment thresholds, and shifting patients with laboratory abnormalities to the outpatient setting, they noted. “At our center a process has been initiated in which the inpatient transplant attending surgeon directly passes off discharged patients to the outpatient team,” the investigators wrote. “Additionally, for patients discharged to an acute rehabilitation facility, a specific transplant physician point of contact is provided to the team at the rehab center in case any questions or issues arise [after] discharge. Although these strategies are a reasonable starting point, follow-up studies remain necessary in order to evaluate the impact of these interventions in this patient cohort.”

The researchers reported no funding sources and had no relevant financial disclosures.

SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

SAN FRANCISCO – Depression and psychosis were strongly correlated in Parkinson’s disease, while the presence of clinical anxiety upped the odds of psychosis by a statistically significant 8%, in a cross-sectional study presented at the 2016 congress of the International Psychogeriatric Association.

Felicia C. Goldstein, PhD, professor of neurology at Emory University, Atlanta, compared 48 patients with Parkinson’s disease and psychosis with 96 nonpsychotic controls who also had Parkinson’s disease. The groups were similar in terms of age, age of disease onset, educational level, Montreal Cognitive Assessment score (MoCA), and Unified Parkinson’s Disease Rating Scale (UPDRS) score, although patients with psychosis had about a 1.5-year longer mean duration of Parkinson’s disease than did controls (8.8 years vs. 7.3 years; P = .06).

Amy Karon/Frontline Medical News

Patients with psychosis were significantly more likely than controls to meet DSM-5 and Beck Depression Inventory II criteria for depression, with odds ratios of 8.0 (95% confidence interval, 2.5-25.6; P = .001) and 1.1 (1.02-1.1; P = .01), respectively. Patients with psychosis also were significantly more likely to have a positive result on the Beck Anxiety Inventory (OR, 1.1; 95% CI, 1.01-1.15; P = .01), and met DSM-5 criteria for anxiety more often than did controls (OR, 3.0; 95% CI, 0.9-9.5), although the latter correlation did not reach statistical significance (P = .07).

“The association between psychosis and anxiety has not been previously reported,” Dr. Goldstein noted. The findings underscore the link between psychosis and mood disorders in Parkinson’s disease and the need to treat these comorbidities, she said.

Neuropsychiatric symptoms in Parkinson’s disease also merit close monitoring and treatment, because they correlate with greater disability, faster progression of motor symptoms, and increased mortality, Adriana P. Hermida, MD, said in a separate oral presentation at the congress. In particular, depression is “the elephant in the room when it comes to Parkinson’s disease,” she said. “It is there, it is underrecognized, and it is undertreated.” Suicidal ideation is common, and patients should be treated even if they do not meet all criteria for a depressive disorder, added Dr. Hermida of the department of psychiatry and behavioral sciences at Emory.

Amy Karon/Frontline Medical News

For depression in Parkinson’s disease, Dr. Hermida said she typically starts with a selective serotonin reuptake inhibitor, most often escitalopram or sertraline. If the patient has a partial response, she adds another antidepressant, but if there is no response, she switches antidepressants. Second-line options for add-ons and switches include mirtazapine, which improves sleep and appetite and may improve tremor; venlafaxine extended release, which can raise blood pressure and may benefit hypotensive patients; and bupropion extended release, which is best for patients who need more activation, do not have substantial concerns with anxiety, and have REM sleep behavior disorder, she said. She said she also will consider dopamine agonists such as pramipexole, but they can increase the risk of psychosis, impulse control disorders, and dopamine dysregulation syndrome. She also noted that electroconvulsive therapy can rapidly improve both depression and motor symptoms, and should not be reserved for last-resort cases. Parkinson’s medications should be held the day of ECT, and cognition should be monitored afterward, she said.

Approximately 30% of Parkinson’s patients meet DSM-5 criteria for an anxiety disorder, and more than half have significant symptoms of anxiety, Dr. Hermida continued. Anxiety, like other signs and symptoms of Parkinson’s disease, can fluctuate throughout the day and tends to occur most frequently during “off” periods. No randomized controlled trials have examined anxiolytics in Parkinson’s disease patients, but studies of mindfulness-based cognitive therapy have yielded good results, she noted. Benzodiazepines “should be used sparingly, if at all,” as they increase the risk of confusion, gait abnormalities, and falls.

Psychosis should be treated if symptoms are ego-dystonic, she said. She said she uses first-line clozapine, which is more effective for delusions than quetiapine and has fewer adverse motor effects. She said she has not yet used pimavanserin (Nuplazid), a selective 5-HT_2A inverse agonist that in April 2016 became the first drug approved by the Food and Drug Administration for treating hallucinations and delusions in Parkinson’s disease. The pivotal trial lasted 6 weeks and included 199 patients; those who received pimavanserin had a median 5.8-point drop on the Scale to Access Psychosis in Parkinson’s Disease (SAPS-PD), compared with 2.7 for placebo (P = .001), Dr. Hermida noted. Patients did not experience sedation or motor impairment, which are common adverse effects of other antipsychotics in this population.

Dr. Goldstein and Dr. Hermida reported no funding sources or conflicts of interest.

SAN FRANCISCO – Depression and psychosis were strongly correlated in Parkinson’s disease, while the presence of clinical anxiety upped the odds of psychosis by a statistically significant 8%, in a cross-sectional study presented at the 2016 congress of the International Psychogeriatric Association.

Felicia C. Goldstein, PhD, professor of neurology at Emory University, Atlanta, compared 48 patients with Parkinson’s disease and psychosis with 96 nonpsychotic controls who also had Parkinson’s disease. The groups were similar in terms of age, age of disease onset, educational level, Montreal Cognitive Assessment score (MoCA), and Unified Parkinson’s Disease Rating Scale (UPDRS) score, although patients with psychosis had about a 1.5-year longer mean duration of Parkinson’s disease than did controls (8.8 years vs. 7.3 years; P = .06).

Amy Karon/Frontline Medical News

Patients with psychosis were significantly more likely than controls to meet DSM-5 and Beck Depression Inventory II criteria for depression, with odds ratios of 8.0 (95% confidence interval, 2.5-25.6; P = .001) and 1.1 (1.02-1.1; P = .01), respectively. Patients with psychosis also were significantly more likely to have a positive result on the Beck Anxiety Inventory (OR, 1.1; 95% CI, 1.01-1.15; P = .01), and met DSM-5 criteria for anxiety more often than did controls (OR, 3.0; 95% CI, 0.9-9.5), although the latter correlation did not reach statistical significance (P = .07).

“The association between psychosis and anxiety has not been previously reported,” Dr. Goldstein noted. The findings underscore the link between psychosis and mood disorders in Parkinson’s disease and the need to treat these comorbidities, she said.

Neuropsychiatric symptoms in Parkinson’s disease also merit close monitoring and treatment, because they correlate with greater disability, faster progression of motor symptoms, and increased mortality, Adriana P. Hermida, MD, said in a separate oral presentation at the congress. In particular, depression is “the elephant in the room when it comes to Parkinson’s disease,” she said. “It is there, it is underrecognized, and it is undertreated.” Suicidal ideation is common, and patients should be treated even if they do not meet all criteria for a depressive disorder, added Dr. Hermida of the department of psychiatry and behavioral sciences at Emory.

Amy Karon/Frontline Medical News

For depression in Parkinson’s disease, Dr. Hermida said she typically starts with a selective serotonin reuptake inhibitor, most often escitalopram or sertraline. If the patient has a partial response, she adds another antidepressant, but if there is no response, she switches antidepressants. Second-line options for add-ons and switches include mirtazapine, which improves sleep and appetite and may improve tremor; venlafaxine extended release, which can raise blood pressure and may benefit hypotensive patients; and bupropion extended release, which is best for patients who need more activation, do not have substantial concerns with anxiety, and have REM sleep behavior disorder, she said. She said she also will consider dopamine agonists such as pramipexole, but they can increase the risk of psychosis, impulse control disorders, and dopamine dysregulation syndrome. She also noted that electroconvulsive therapy can rapidly improve both depression and motor symptoms, and should not be reserved for last-resort cases. Parkinson’s medications should be held the day of ECT, and cognition should be monitored afterward, she said.

Approximately 30% of Parkinson’s patients meet DSM-5 criteria for an anxiety disorder, and more than half have significant symptoms of anxiety, Dr. Hermida continued. Anxiety, like other signs and symptoms of Parkinson’s disease, can fluctuate throughout the day and tends to occur most frequently during “off” periods. No randomized controlled trials have examined anxiolytics in Parkinson’s disease patients, but studies of mindfulness-based cognitive therapy have yielded good results, she noted. Benzodiazepines “should be used sparingly, if at all,” as they increase the risk of confusion, gait abnormalities, and falls.

Psychosis should be treated if symptoms are ego-dystonic, she said. She said she uses first-line clozapine, which is more effective for delusions than quetiapine and has fewer adverse motor effects. She said she has not yet used pimavanserin (Nuplazid), a selective 5-HT_2A inverse agonist that in April 2016 became the first drug approved by the Food and Drug Administration for treating hallucinations and delusions in Parkinson’s disease. The pivotal trial lasted 6 weeks and included 199 patients; those who received pimavanserin had a median 5.8-point drop on the Scale to Access Psychosis in Parkinson’s Disease (SAPS-PD), compared with 2.7 for placebo (P = .001), Dr. Hermida noted. Patients did not experience sedation or motor impairment, which are common adverse effects of other antipsychotics in this population.

Dr. Goldstein and Dr. Hermida reported no funding sources or conflicts of interest.

SAN FRANCISCO – Depression and psychosis were strongly correlated in Parkinson’s disease, while the presence of clinical anxiety upped the odds of psychosis by a statistically significant 8%, in a cross-sectional study presented at the 2016 congress of the International Psychogeriatric Association.

Felicia C. Goldstein, PhD, professor of neurology at Emory University, Atlanta, compared 48 patients with Parkinson’s disease and psychosis with 96 nonpsychotic controls who also had Parkinson’s disease. The groups were similar in terms of age, age of disease onset, educational level, Montreal Cognitive Assessment score (MoCA), and Unified Parkinson’s Disease Rating Scale (UPDRS) score, although patients with psychosis had about a 1.5-year longer mean duration of Parkinson’s disease than did controls (8.8 years vs. 7.3 years; P = .06).

Amy Karon/Frontline Medical News

Patients with psychosis were significantly more likely than controls to meet DSM-5 and Beck Depression Inventory II criteria for depression, with odds ratios of 8.0 (95% confidence interval, 2.5-25.6; P = .001) and 1.1 (1.02-1.1; P = .01), respectively. Patients with psychosis also were significantly more likely to have a positive result on the Beck Anxiety Inventory (OR, 1.1; 95% CI, 1.01-1.15; P = .01), and met DSM-5 criteria for anxiety more often than did controls (OR, 3.0; 95% CI, 0.9-9.5), although the latter correlation did not reach statistical significance (P = .07).

“The association between psychosis and anxiety has not been previously reported,” Dr. Goldstein noted. The findings underscore the link between psychosis and mood disorders in Parkinson’s disease and the need to treat these comorbidities, she said.

Neuropsychiatric symptoms in Parkinson’s disease also merit close monitoring and treatment, because they correlate with greater disability, faster progression of motor symptoms, and increased mortality, Adriana P. Hermida, MD, said in a separate oral presentation at the congress. In particular, depression is “the elephant in the room when it comes to Parkinson’s disease,” she said. “It is there, it is underrecognized, and it is undertreated.” Suicidal ideation is common, and patients should be treated even if they do not meet all criteria for a depressive disorder, added Dr. Hermida of the department of psychiatry and behavioral sciences at Emory.

Amy Karon/Frontline Medical News

For depression in Parkinson’s disease, Dr. Hermida said she typically starts with a selective serotonin reuptake inhibitor, most often escitalopram or sertraline. If the patient has a partial response, she adds another antidepressant, but if there is no response, she switches antidepressants. Second-line options for add-ons and switches include mirtazapine, which improves sleep and appetite and may improve tremor; venlafaxine extended release, which can raise blood pressure and may benefit hypotensive patients; and bupropion extended release, which is best for patients who need more activation, do not have substantial concerns with anxiety, and have REM sleep behavior disorder, she said. She said she also will consider dopamine agonists such as pramipexole, but they can increase the risk of psychosis, impulse control disorders, and dopamine dysregulation syndrome. She also noted that electroconvulsive therapy can rapidly improve both depression and motor symptoms, and should not be reserved for last-resort cases. Parkinson’s medications should be held the day of ECT, and cognition should be monitored afterward, she said.

Approximately 30% of Parkinson’s patients meet DSM-5 criteria for an anxiety disorder, and more than half have significant symptoms of anxiety, Dr. Hermida continued. Anxiety, like other signs and symptoms of Parkinson’s disease, can fluctuate throughout the day and tends to occur most frequently during “off” periods. No randomized controlled trials have examined anxiolytics in Parkinson’s disease patients, but studies of mindfulness-based cognitive therapy have yielded good results, she noted. Benzodiazepines “should be used sparingly, if at all,” as they increase the risk of confusion, gait abnormalities, and falls.

Psychosis should be treated if symptoms are ego-dystonic, she said. She said she uses first-line clozapine, which is more effective for delusions than quetiapine and has fewer adverse motor effects. She said she has not yet used pimavanserin (Nuplazid), a selective 5-HT_2A inverse agonist that in April 2016 became the first drug approved by the Food and Drug Administration for treating hallucinations and delusions in Parkinson’s disease. The pivotal trial lasted 6 weeks and included 199 patients; those who received pimavanserin had a median 5.8-point drop on the Scale to Access Psychosis in Parkinson’s Disease (SAPS-PD), compared with 2.7 for placebo (P = .001), Dr. Hermida noted. Patients did not experience sedation or motor impairment, which are common adverse effects of other antipsychotics in this population.

Dr. Goldstein and Dr. Hermida reported no funding sources or conflicts of interest.