Diana Mahoney

Major Finding: Systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function.

Data Source: An analysis of 499 older Canadian adults, 41 with diabetes, drawn from the Victoria Longitudinal Study of human aging.

Disclosures: The authors reported no financial conflicts of interest. The study was sponsored by the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a recent report.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from an ongoing multicohort study comprising community-dwelling adults from Western Canada. Participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants, who were compared with the 458 participants without diabetes. No group differences were found for global cognition or visual or audio acuity, said C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. Type 2 diabetes “may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote.

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies,” they concluded.

Major Finding: Systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function.

Data Source: An analysis of 499 older Canadian adults, 41 with diabetes, drawn from the Victoria Longitudinal Study of human aging.

Disclosures: The authors reported no financial conflicts of interest. The study was sponsored by the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a recent report.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from an ongoing multicohort study comprising community-dwelling adults from Western Canada. Participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants, who were compared with the 458 participants without diabetes. No group differences were found for global cognition or visual or audio acuity, said C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. Type 2 diabetes “may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote.

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies,” they concluded.

Major Finding: Systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function.

Data Source: An analysis of 499 older Canadian adults, 41 with diabetes, drawn from the Victoria Longitudinal Study of human aging.

Disclosures: The authors reported no financial conflicts of interest. The study was sponsored by the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a recent report.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from an ongoing multicohort study comprising community-dwelling adults from Western Canada. Participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study's third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer's disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants, who were compared with the 458 participants without diabetes. No group differences were found for global cognition or visual or audio acuity, said C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%–50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%–50% of performance on five different cognitive tests. Type 2 diabetes “may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote.

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies,” they concluded.

BOSTON – Preoperative nasal carriage of methicillin-resistant Staphylococcus aureus increases the risk of postsurgical infection despite prophylaxis with vancomycin, based on a study of more than 4,000 patients.

The findings confirm the utility of preoperative screening for MRSA nasal carriage and suggest that patients who test positive may benefit from additional interventions to prevent postoperative infections, Dr. Kalpana Gupta reported at the conference.

To assess the relationship between preoperative nasal MRSA carriage, prophylactic antibiotics, and postoperative surgical infections and cultures, Dr. Gupta of the VA Boston Healthcare System and her colleagues retrospectively studied all patients in the nine-campus system’s veteran population who had a clean or clean-contaminated surgical procedure between Jan. 1, 2008, and Dec. 31, 2009, and who had undergone MRSA screening within 31 days of surgery.

The data extracted from the VA electronic health records included:

• MRSA nasal status within 31 days before and after surgery.

• MRSA nasal status and culture status in the year before surgery.

• Date, type, and American Society of Anesthesiologists (ASA) class of surgery.

• Duration of procedure.

• Surgical skin preparation used.

• Postoperative outcomes, including MRSA, methicillin-sensitive S. aureus, and other organisms, within 1 year after surgery.

• National Surgical Quality Improvement Program data with risk factors of interest, comorbidities, and postoperative complications.

• Perioperative prophylaxis agents, including vancomycin, cefazolin, and other antibiotics.

Of the 4,238 surgical patients who had undergone a nasal swab in the month before surgery, 279 were MRSA nasal positive and 3,959 were MRSA nasal negative. Postoperatively, 12% of the nasal-positive patients had a MRSA-positive clinical culture within 31 days, compared with 0.75% of the nasal-negative patients – a difference that remained significant when stratified by surgery type and ASA class, Dr. Gupta reported. Similarly, the nasal-positive patients were significantly more likely to have any type of MRSA infection as well as a MRSA surgical infection in the month after surgery, she said at the conference sponsored by the American Society for Microbiology.

Among all of the patients, neither vancomycin nor cefazolin prophylaxis protected against positive MRSA cultures or infections, nor did the use of chlorhexidine scrub in the operating room, Dr. Gupta noted, stating “we already take a lot of preventive measures, but those measures may not be enough.”

The findings highlight the need for decolonization strategies in MRSA-colonized patients, particularly those undergoing higher-risk procedures, Dr. Gupta stated. Given the possibility that decolonization efforts could lead to the development of resistance in MRSA, the investigators plan to conduct further research using MRSA isolates to study how resistance develops, she said.

The findings of the study are limited by the low overall infection rate, according to Dr. Gupta, who noted that higher numbers would have provided more insight into the efficacy of prophylactic strategies.

BOSTON – Preoperative nasal carriage of methicillin-resistant Staphylococcus aureus increases the risk of postsurgical infection despite prophylaxis with vancomycin, based on a study of more than 4,000 patients.

The findings confirm the utility of preoperative screening for MRSA nasal carriage and suggest that patients who test positive may benefit from additional interventions to prevent postoperative infections, Dr. Kalpana Gupta reported at the conference.

To assess the relationship between preoperative nasal MRSA carriage, prophylactic antibiotics, and postoperative surgical infections and cultures, Dr. Gupta of the VA Boston Healthcare System and her colleagues retrospectively studied all patients in the nine-campus system’s veteran population who had a clean or clean-contaminated surgical procedure between Jan. 1, 2008, and Dec. 31, 2009, and who had undergone MRSA screening within 31 days of surgery.

The data extracted from the VA electronic health records included:

• MRSA nasal status within 31 days before and after surgery.

• MRSA nasal status and culture status in the year before surgery.

• Date, type, and American Society of Anesthesiologists (ASA) class of surgery.

• Duration of procedure.

• Surgical skin preparation used.

• Postoperative outcomes, including MRSA, methicillin-sensitive S. aureus, and other organisms, within 1 year after surgery.

• National Surgical Quality Improvement Program data with risk factors of interest, comorbidities, and postoperative complications.

• Perioperative prophylaxis agents, including vancomycin, cefazolin, and other antibiotics.

Of the 4,238 surgical patients who had undergone a nasal swab in the month before surgery, 279 were MRSA nasal positive and 3,959 were MRSA nasal negative. Postoperatively, 12% of the nasal-positive patients had a MRSA-positive clinical culture within 31 days, compared with 0.75% of the nasal-negative patients – a difference that remained significant when stratified by surgery type and ASA class, Dr. Gupta reported. Similarly, the nasal-positive patients were significantly more likely to have any type of MRSA infection as well as a MRSA surgical infection in the month after surgery, she said at the conference sponsored by the American Society for Microbiology.

Among all of the patients, neither vancomycin nor cefazolin prophylaxis protected against positive MRSA cultures or infections, nor did the use of chlorhexidine scrub in the operating room, Dr. Gupta noted, stating “we already take a lot of preventive measures, but those measures may not be enough.”

The findings highlight the need for decolonization strategies in MRSA-colonized patients, particularly those undergoing higher-risk procedures, Dr. Gupta stated. Given the possibility that decolonization efforts could lead to the development of resistance in MRSA, the investigators plan to conduct further research using MRSA isolates to study how resistance develops, she said.

The findings of the study are limited by the low overall infection rate, according to Dr. Gupta, who noted that higher numbers would have provided more insight into the efficacy of prophylactic strategies.

BOSTON – Preoperative nasal carriage of methicillin-resistant Staphylococcus aureus increases the risk of postsurgical infection despite prophylaxis with vancomycin, based on a study of more than 4,000 patients.

The findings confirm the utility of preoperative screening for MRSA nasal carriage and suggest that patients who test positive may benefit from additional interventions to prevent postoperative infections, Dr. Kalpana Gupta reported at the conference.

To assess the relationship between preoperative nasal MRSA carriage, prophylactic antibiotics, and postoperative surgical infections and cultures, Dr. Gupta of the VA Boston Healthcare System and her colleagues retrospectively studied all patients in the nine-campus system’s veteran population who had a clean or clean-contaminated surgical procedure between Jan. 1, 2008, and Dec. 31, 2009, and who had undergone MRSA screening within 31 days of surgery.

The data extracted from the VA electronic health records included:

• MRSA nasal status within 31 days before and after surgery.

• MRSA nasal status and culture status in the year before surgery.

• Date, type, and American Society of Anesthesiologists (ASA) class of surgery.

• Duration of procedure.

• Surgical skin preparation used.

• Postoperative outcomes, including MRSA, methicillin-sensitive S. aureus, and other organisms, within 1 year after surgery.

• National Surgical Quality Improvement Program data with risk factors of interest, comorbidities, and postoperative complications.

• Perioperative prophylaxis agents, including vancomycin, cefazolin, and other antibiotics.

Of the 4,238 surgical patients who had undergone a nasal swab in the month before surgery, 279 were MRSA nasal positive and 3,959 were MRSA nasal negative. Postoperatively, 12% of the nasal-positive patients had a MRSA-positive clinical culture within 31 days, compared with 0.75% of the nasal-negative patients – a difference that remained significant when stratified by surgery type and ASA class, Dr. Gupta reported. Similarly, the nasal-positive patients were significantly more likely to have any type of MRSA infection as well as a MRSA surgical infection in the month after surgery, she said at the conference sponsored by the American Society for Microbiology.

Among all of the patients, neither vancomycin nor cefazolin prophylaxis protected against positive MRSA cultures or infections, nor did the use of chlorhexidine scrub in the operating room, Dr. Gupta noted, stating “we already take a lot of preventive measures, but those measures may not be enough.”

The findings highlight the need for decolonization strategies in MRSA-colonized patients, particularly those undergoing higher-risk procedures, Dr. Gupta stated. Given the possibility that decolonization efforts could lead to the development of resistance in MRSA, the investigators plan to conduct further research using MRSA isolates to study how resistance develops, she said.

The findings of the study are limited by the low overall infection rate, according to Dr. Gupta, who noted that higher numbers would have provided more insight into the efficacy of prophylactic strategies.

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.

Because early, aggressive treatment in rheumatoid arthritis is associated with better long-term outcomes, the identification of markers of disease course and treatment response is a primary research goal. Toward this end, investigators at Brigham and Women’s Hospital in Boston have been systematically collecting detailed clinical, serologic, environmental, and genetic information on RA patients since 2003 as part of a prospective, observational cohort called the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry.

To date, more than 1,100 RA patients from the hospital’s arthritis center with new-onset or established disease have been recruited for participation, which includes baseline and annual clinic visits to collect information on demographics, disease activity, medication use, comorbidities, functional status, disability, quality of life, and health care resource utilization; blood samples (including serum, RNA, and DNA); and hand and wrist radiographs every 2 years. Additionally, patients are asked to complete self-administered questionnaires 6 months after their annual appointments to provide information about medication use or changes, functional status, new symptoms, and health care resource use, according to the BRASS investigators (Rheumatology 2010 Sep 16. [doi: 10.1093/rheumatology/keq263]).

The registry, funded by a grant from Millenium Pharmaceuticals, Biogen Idec, and Crescendo Bioscience, “has become an important component of local, national, and international research collaborations seeking reliable scientific evidence,” according to Dr. Nancy A. Shadick, a rheumatologist at Brigham and Women’s Hospital and BRASS principal investigator. Dr. Shadick offers insight into the BRASS registry and discusses some important research that has come out of the registry as well as the challenges of clinical and genetic research in patient registries.

Question: How is the BRASS registry unique relative to other patient registries/cohort studies that collect data on rheumatic diseases and DMARD treatment?

Dr. Shadick: National and international registries of RA patients are instrumental in the collection of data regarding treatment efficacy. There are approximately 10 patient registries/cohort studies collecting data on rheumatic diseases and DMARD therapy, but not all of them collect additional laboratory tests beyond C-reactive protein, erythrocyte sedimentation rate, or additional patient clinical measures like the 28-joint DAS-CRP3 (DAS-28-CRP3). BRASS was developed to determine markers of treatment response and drug toxicity through the assessment of clinical variables and inherited genetic variants and patterns of gene expression, therefore the registry collects over 1,200 clinical variables, including lung function, periodontal health, sleep quality, mental health measures, cost effectiveness, and other patient-reported outcomes. Additionally, it collects hand radiographic data every 2 years, and it has comprehensive and complete genetic, serologic, and RNA expression capabilities on each of the cohort members. It has excellent cohort retention (more than 80% after 5 years) and very accurate medication data. The cohort offers the ability to determine biomarker and genetic predictors of drug response and toxicity and also the ability to report on the contemporary natural history of “treated RA.”

Question: In what ways has the BRASS data been used to date to gain insight into RA patients’ treatment response to DMARDs?

Dr. Shadick: Two recent papers come to mind. The first examined the association between candidate SNPS and disease activity in RA patients on methotrexate. The investigators found that patients carrying the minor allele of an ATIC single nucleotide polymorphism (SNP) were more likely to have lower disease activity after adjustment for other confounders (Rheumatology (Oxford) 2009;48:613-7). Similarly, in a multicohort study which included BRASS samples, those individuals with the protein tyrosinde phosphatase receptor type C (also known as the CD45 gene) had a better response to anti–tumor necrosis factor therapy than did those without the CD45 gene (Mol. Med. 2009;15:136-43).

Question: How have the genetic data been used in research to date?

Dr. Shadick: Our genetic researchers have analyzed the cohort using genome-wide association studies (GWAS) analyses which allow screening of a large number of genes, or SNPs, that are potentially associated with a number of RA outcomes. Pooling the results with other cohorts as well as controls without RA, the BRASS cohort data has helped determine new susceptibility genes for RA, genes that predict disease severity, nonerosive disease in RA, and earlier onset of RA.

Question: What are some of the clinical or genetic questions that the BRASS registry might help answer down the line?

Dr. Shadick: We would like to look more closely at gene/environment interactions that result in some RA comorbidities such as infection, certain cancers, RA that never erodes bone despite disease activity, and genetic predictors for RA-induced interstitial lung disease.

Question: What have been some of the challenges in the development, maintenance, and application of BRASS registry data?

Dr. Shadick: Maintaining a large patient database takes a “village.” In this case, that means a well organized team of researchers, devoted doctors who contribute information about their patients, and devoted RA patients who tirelessly remain in the study and fill out forms. However, many of the participants and the rheumatologists find participating in the BRASS registry rewarding, particularly when new scientific discovery occurs from the data. There are a few limitations in using registry data. For example, registry data (unlike randomized controlled trials) often lack the ability to evaluate drug efficacy. On the other hand, observational registries are more representative of the real-world population, and as such we are observing instead “real world effectiveness.”

This column, “Ask the Expert,” regularly appears in Rheumatology News, an Elsevier publication. Dr. Nancy A. Shadick is a clinical researcher and rheumatologist at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School in Boston. She has received research grant support from Biogen Idec, Crescendo Biosciences, and Amgen.

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Major Finding: Pulmonary involvement is common in patients with juvenile dermatomyositis and is associated with cumulative organ damage and patient-reported health status.

Data Source: Case-control study comprising a retrospective inception cohort of 59 Norwegian patients diagnosed with JDM, and healthy controls.

Disclosures: The authors reported having no financial conflicts of interest. The project received financial support from the Dr. Olga Imerslunds Foundation, Oslo.

Juvenile dermatomyositis is associated with reduced lung volumes, restrictive ventilatory defects, and evidence of pulmonary abnormalities on high-resolution CT, a study has shown.

The pulmonary complications — even in the absence of lung symptoms — correlated with cumulative organ damage and patient-reported health status, which demonstrates the clinical relevance of the findings and the systemic nature of the chronic vasculopathic disease, reported Dr. Helga Sanner of the division of rheumatology at the University of Oslo and her associates.

Because of the scarcity of data on pulmonary involvement in juvenile dermatomyositis, Dr. Sanner and colleagues designed a case-control study to compare lung function in a cohort of patients with juvenile dermatomyositis (JDM) vs. matched controls. The investigators also determined the prevalence of and correlation between pulmonary function impairments and abnormalities on high-resolution computed tomography (HRCT).

The investigators enrolled 59 patients whose JDM was diagnosed between January 1970 and June 2006 (identified from a retrospective inception cohort) and 59 age- and sex-matched controls.

Both the JDM patients and the controls underwent clinical examination by a single doctor, including pulmonary function testing (measurement of gas diffusion and body plethysmography) and assessment of blood samples.

The JDM patients also underwent HRCT, anti—nuclear antibody analysis, measurement of disease activity using the Disease Activity Score (DAS) for JDM, assessment of cumulative organ damage using the Myositis Damage Index (MDI), measurement of physical health using the Short Form-36 physical component summary (PCS), and measurement of physical function using the Health Assessment Questionnaire (HAQ) for patients aged 18 years and older and the Child HAQ for patients younger than 18 years.

With respect to clinical lung involvement, three of the JDM patients had been diagnosed with interstitial lung disease (ILD) prior to the clinical examination; 6 months after her JDM diagnosis, one of the JDM patients developed mediastinal emphysema without evidence of ILD at the age of 15 years, the authors wrote, noting that none of the controls had lung symptoms.

Compared with the controls, the JDM patients had significantly lower total lung capacity (TLC), diffusion lung capacity of carbon monoxide (DLCO), forced vital capacity (FVC), and the forced expiratory volume in 1 second (FEV₁). Approximately 26% of the JDM patients, compared with 9% of the controls, had a low TLC; 49% of the JDM patients, compared with 8% of the controls, had a low DLCO (defined for both measures as less than the fifth percentile of the predicted values), the authors reported (Ann Rheum Dis. 2010 Aug. 30 [doi:10.1136/ard.2010.131433]).

With respect to HRCT findings in the JDM patients, 37% had evidence of pulmonary abnormalities, including changes compatible with interstitial lung disease (14%), airway disease (15%), pleural thickening (5%), and calcinosis in the chest wall (14%), the authors reported.

The correlation analyses showed that 50% of patients with an abnormal HRCT abnormality had a low TLC, compared with 12% of patients with normal HRCT findings, and 57% of patients with HRCT-detected calcinosis in muscle and/or fascia had a low TLC, compared with 22% of patients without that finding. The TLC percentage of predicted correlated with HRCT-detected airway disease, whereas the DLCO percentage of predicted did not correlate with any HRCT variables.

“The association between chest wall calcinosis and restriction is not surprising, since calcium deposits might lead to respiratory muscle impairment, however the association between a low TLC and airway disease [for example, bronchiectasis] is more difficult to explain,” the authors wrote, noting the possibility of a type I error.

HRCT abnormalities also correlated with cumulative organ damage and poorer patient-reported health status as measured by total MDI, HAQ/child-HAQ, and SF-36 PCS, and a borderline association was found between HRCT-detected ILD and dyspnea on exertion. “Taken together, we believe this supports the clinical relevance of our findings,” the authors wrote.

Even though approximately 75% of the patients had impaired diffusion, restriction, or HRCT abnormality at follow-up, most of the patients did not report lung symptoms. It's possible “that the lung symptoms may have been masked by restricted functions in other organ systems,” the authors speculated. For example, “if patients are not able to complete physical exercise due to muscle weakness, they will not experience shortness of breath even when they have reduced lung function,” they stated.

Follow-up studies are needed to investigate whether more patients with detectable HRCT abnormalities and pulmonary function test impairments will develop clinically manifest pulmonary disease in the future, they stressed.

The findings are limited by the study's retrospective assessment of early disease variables and by the lack of longitudinal data on the outcome measures, according to the authors. Because symptomatic ILD can develop in the chronic phases of the disease, they wrote, “some of our latest diagnosed patients may still develop ILD.” The study is also limited by the retrospective assessment of early disease variables.

Major Finding: Pulmonary involvement is common in patients with juvenile dermatomyositis and is associated with cumulative organ damage and patient-reported health status.

Data Source: Case-control study comprising a retrospective inception cohort of 59 Norwegian patients diagnosed with JDM, and healthy controls.

Disclosures: The authors reported having no financial conflicts of interest. The project received financial support from the Dr. Olga Imerslunds Foundation, Oslo.

Juvenile dermatomyositis is associated with reduced lung volumes, restrictive ventilatory defects, and evidence of pulmonary abnormalities on high-resolution CT, a study has shown.

The pulmonary complications — even in the absence of lung symptoms — correlated with cumulative organ damage and patient-reported health status, which demonstrates the clinical relevance of the findings and the systemic nature of the chronic vasculopathic disease, reported Dr. Helga Sanner of the division of rheumatology at the University of Oslo and her associates.

Because of the scarcity of data on pulmonary involvement in juvenile dermatomyositis, Dr. Sanner and colleagues designed a case-control study to compare lung function in a cohort of patients with juvenile dermatomyositis (JDM) vs. matched controls. The investigators also determined the prevalence of and correlation between pulmonary function impairments and abnormalities on high-resolution computed tomography (HRCT).

The investigators enrolled 59 patients whose JDM was diagnosed between January 1970 and June 2006 (identified from a retrospective inception cohort) and 59 age- and sex-matched controls.

Both the JDM patients and the controls underwent clinical examination by a single doctor, including pulmonary function testing (measurement of gas diffusion and body plethysmography) and assessment of blood samples.

The JDM patients also underwent HRCT, anti—nuclear antibody analysis, measurement of disease activity using the Disease Activity Score (DAS) for JDM, assessment of cumulative organ damage using the Myositis Damage Index (MDI), measurement of physical health using the Short Form-36 physical component summary (PCS), and measurement of physical function using the Health Assessment Questionnaire (HAQ) for patients aged 18 years and older and the Child HAQ for patients younger than 18 years.

With respect to clinical lung involvement, three of the JDM patients had been diagnosed with interstitial lung disease (ILD) prior to the clinical examination; 6 months after her JDM diagnosis, one of the JDM patients developed mediastinal emphysema without evidence of ILD at the age of 15 years, the authors wrote, noting that none of the controls had lung symptoms.

Compared with the controls, the JDM patients had significantly lower total lung capacity (TLC), diffusion lung capacity of carbon monoxide (DLCO), forced vital capacity (FVC), and the forced expiratory volume in 1 second (FEV₁). Approximately 26% of the JDM patients, compared with 9% of the controls, had a low TLC; 49% of the JDM patients, compared with 8% of the controls, had a low DLCO (defined for both measures as less than the fifth percentile of the predicted values), the authors reported (Ann Rheum Dis. 2010 Aug. 30 [doi:10.1136/ard.2010.131433]).

With respect to HRCT findings in the JDM patients, 37% had evidence of pulmonary abnormalities, including changes compatible with interstitial lung disease (14%), airway disease (15%), pleural thickening (5%), and calcinosis in the chest wall (14%), the authors reported.

The correlation analyses showed that 50% of patients with an abnormal HRCT abnormality had a low TLC, compared with 12% of patients with normal HRCT findings, and 57% of patients with HRCT-detected calcinosis in muscle and/or fascia had a low TLC, compared with 22% of patients without that finding. The TLC percentage of predicted correlated with HRCT-detected airway disease, whereas the DLCO percentage of predicted did not correlate with any HRCT variables.

“The association between chest wall calcinosis and restriction is not surprising, since calcium deposits might lead to respiratory muscle impairment, however the association between a low TLC and airway disease [for example, bronchiectasis] is more difficult to explain,” the authors wrote, noting the possibility of a type I error.

HRCT abnormalities also correlated with cumulative organ damage and poorer patient-reported health status as measured by total MDI, HAQ/child-HAQ, and SF-36 PCS, and a borderline association was found between HRCT-detected ILD and dyspnea on exertion. “Taken together, we believe this supports the clinical relevance of our findings,” the authors wrote.

Even though approximately 75% of the patients had impaired diffusion, restriction, or HRCT abnormality at follow-up, most of the patients did not report lung symptoms. It's possible “that the lung symptoms may have been masked by restricted functions in other organ systems,” the authors speculated. For example, “if patients are not able to complete physical exercise due to muscle weakness, they will not experience shortness of breath even when they have reduced lung function,” they stated.

Follow-up studies are needed to investigate whether more patients with detectable HRCT abnormalities and pulmonary function test impairments will develop clinically manifest pulmonary disease in the future, they stressed.

The findings are limited by the study's retrospective assessment of early disease variables and by the lack of longitudinal data on the outcome measures, according to the authors. Because symptomatic ILD can develop in the chronic phases of the disease, they wrote, “some of our latest diagnosed patients may still develop ILD.” The study is also limited by the retrospective assessment of early disease variables.

Major Finding: Pulmonary involvement is common in patients with juvenile dermatomyositis and is associated with cumulative organ damage and patient-reported health status.

Data Source: Case-control study comprising a retrospective inception cohort of 59 Norwegian patients diagnosed with JDM, and healthy controls.

Disclosures: The authors reported having no financial conflicts of interest. The project received financial support from the Dr. Olga Imerslunds Foundation, Oslo.

Juvenile dermatomyositis is associated with reduced lung volumes, restrictive ventilatory defects, and evidence of pulmonary abnormalities on high-resolution CT, a study has shown.

The pulmonary complications — even in the absence of lung symptoms — correlated with cumulative organ damage and patient-reported health status, which demonstrates the clinical relevance of the findings and the systemic nature of the chronic vasculopathic disease, reported Dr. Helga Sanner of the division of rheumatology at the University of Oslo and her associates.

Because of the scarcity of data on pulmonary involvement in juvenile dermatomyositis, Dr. Sanner and colleagues designed a case-control study to compare lung function in a cohort of patients with juvenile dermatomyositis (JDM) vs. matched controls. The investigators also determined the prevalence of and correlation between pulmonary function impairments and abnormalities on high-resolution computed tomography (HRCT).

The investigators enrolled 59 patients whose JDM was diagnosed between January 1970 and June 2006 (identified from a retrospective inception cohort) and 59 age- and sex-matched controls.

Both the JDM patients and the controls underwent clinical examination by a single doctor, including pulmonary function testing (measurement of gas diffusion and body plethysmography) and assessment of blood samples.

The JDM patients also underwent HRCT, anti—nuclear antibody analysis, measurement of disease activity using the Disease Activity Score (DAS) for JDM, assessment of cumulative organ damage using the Myositis Damage Index (MDI), measurement of physical health using the Short Form-36 physical component summary (PCS), and measurement of physical function using the Health Assessment Questionnaire (HAQ) for patients aged 18 years and older and the Child HAQ for patients younger than 18 years.

With respect to clinical lung involvement, three of the JDM patients had been diagnosed with interstitial lung disease (ILD) prior to the clinical examination; 6 months after her JDM diagnosis, one of the JDM patients developed mediastinal emphysema without evidence of ILD at the age of 15 years, the authors wrote, noting that none of the controls had lung symptoms.

Compared with the controls, the JDM patients had significantly lower total lung capacity (TLC), diffusion lung capacity of carbon monoxide (DLCO), forced vital capacity (FVC), and the forced expiratory volume in 1 second (FEV₁). Approximately 26% of the JDM patients, compared with 9% of the controls, had a low TLC; 49% of the JDM patients, compared with 8% of the controls, had a low DLCO (defined for both measures as less than the fifth percentile of the predicted values), the authors reported (Ann Rheum Dis. 2010 Aug. 30 [doi:10.1136/ard.2010.131433]).

With respect to HRCT findings in the JDM patients, 37% had evidence of pulmonary abnormalities, including changes compatible with interstitial lung disease (14%), airway disease (15%), pleural thickening (5%), and calcinosis in the chest wall (14%), the authors reported.

The correlation analyses showed that 50% of patients with an abnormal HRCT abnormality had a low TLC, compared with 12% of patients with normal HRCT findings, and 57% of patients with HRCT-detected calcinosis in muscle and/or fascia had a low TLC, compared with 22% of patients without that finding. The TLC percentage of predicted correlated with HRCT-detected airway disease, whereas the DLCO percentage of predicted did not correlate with any HRCT variables.

“The association between chest wall calcinosis and restriction is not surprising, since calcium deposits might lead to respiratory muscle impairment, however the association between a low TLC and airway disease [for example, bronchiectasis] is more difficult to explain,” the authors wrote, noting the possibility of a type I error.

HRCT abnormalities also correlated with cumulative organ damage and poorer patient-reported health status as measured by total MDI, HAQ/child-HAQ, and SF-36 PCS, and a borderline association was found between HRCT-detected ILD and dyspnea on exertion. “Taken together, we believe this supports the clinical relevance of our findings,” the authors wrote.

Even though approximately 75% of the patients had impaired diffusion, restriction, or HRCT abnormality at follow-up, most of the patients did not report lung symptoms. It's possible “that the lung symptoms may have been masked by restricted functions in other organ systems,” the authors speculated. For example, “if patients are not able to complete physical exercise due to muscle weakness, they will not experience shortness of breath even when they have reduced lung function,” they stated.

Follow-up studies are needed to investigate whether more patients with detectable HRCT abnormalities and pulmonary function test impairments will develop clinically manifest pulmonary disease in the future, they stressed.

The findings are limited by the study's retrospective assessment of early disease variables and by the lack of longitudinal data on the outcome measures, according to the authors. Because symptomatic ILD can develop in the chronic phases of the disease, they wrote, “some of our latest diagnosed patients may still develop ILD.” The study is also limited by the retrospective assessment of early disease variables.

BOSTON — Sleep disturbances may be an important target for treating posttraumatic stress disorder, according to Dr. R. Bruce Lydiard of the Medical University of South Carolina in Charleston.

Persistent, severe posttraumatic nightmares, REM sleep fragmentation, insomnia, excessive nocturnal periodic limb movements, and sleep-disordered breathing are frequently experienced by individuals with PTSD, Dr. Lydiard said. Although these sleep problems are often viewed as secondary symptoms of PTSD, “the evidence suggests that after a traumatic event, sleep disruption appears before the onset of PTSD and may be a risk factor for it,” he proposed.

Polysomnographic data from 21 individuals with traumatic injuries showed that the number of REM periods and the (shorter) duration of REM periods within 1 month after the traumatic event were predictive of PTSD symptom severity 6 weeks later (Am. J. Psychiatry. 2002;159:1696–701).

Neurobiologically, the association makes sense, Dr. Lydiard said. “Sleep is regulated in part by brain areas in which PTSD-related changes occur,” which suggests that the stress response in PTSD and sleep dysfunction may be biologically linked.

Imaging studies suggest that exposure to trauma-related stimuli leads to hyperactivation in the amygdala and decreased activation in the medial prefrontal cortex/anterior cingulate cortex and hippocampus, with the magnitude of the activation correlating with the clinical severity of PTSD symptoms.

Polysomnographic investigations in patients with PTSD and sleep disturbances have revealed increased REM density, reduced REM duration, and increased motor activity, Dr. Lydiard said.

Together with clinical reports, “these data provide the basis for REM sleep dysregulation as a core feature in PTSD,” whereby increased activity in the amygdala and decreased inhibitory input from the medial prefrontal cortex lead to a persistently overactive noradrenergic system. “As a result, the usual rhythm of REM-NREM sleep is disrupted, and REM sleep is fragmented,” he said.

Based on this model, investigators have hypothesized that targeting noradrenergic signaling during or near REM episodes may normalize REM sleep, which in turn might improve PTSD sleep disturbances and, potentially, other PTSD symptoms, Dr. Lydiard said.

The alpha adrenergic antagonist prazosin has shown promise in multiple case and chart reviews, open-label trials, and placebo-controlled studies.

In one trial of 40 veterans with PTSD sleep disturbance, patients who were randomized to receive a nightly dose of prazosin — originally marketed as an antihypertensive agent — reported significant improvements in sleep quality and significant reductions in trauma nightmares, as well a better overall sense of well-being and improved daily functioning (Biol. Psychiatry 2007;61:928–34).

In another study, investigators evaluated the effect of prazosin vs. placebo on objective sleep parameters in 13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbance. The prazosin group experienced significantly increased total sleep time as well as increased REM sleep time and mean REM period duration (Biol. Psychiatry 2008;63:629–32).

In the various studies, the therapeutic benefit of prazosin was achieved within 1–2 weeks “with doses as low as 1 mg nightly,” Dr. Lydiard said.

In addition to improving sleep measures, prazosin may be useful for other trauma-related symptoms. In a small study of PTSD subjects whose nightmares were well controlled with the drug, the addition of small daytime doses lessened patients' reactivity to trauma cues during the day, he said (Biol. Psychiatry 2006;59:577–81). This finding “adds to the growing body of evidence that targeting sleep in PTSD is clinically relevant.”

Although some evidence exists to support the use of other antiadrenergic agents such as clonidine and guanfacine—as well as the anticonvulsant gabapentin—in PTSD, “large, randomized controlled trials are needed to clarify the role” of all of these agents, Dr. Lydiard said.

Additional studies also are warranted, he said, to investigate nonpharmacologic approaches to improving PTSD sleep disturbance, such as the use of imagery rehearsal therapy, which has demonstrated efficacy in small studies (J. Trauma. Stress 2009;22:236–9).

Dr. Lydiard disclosed receiving honoraria from Reed Medical Education, the logistics collaborator for the Massachusetts General Hospital Psychiatry Academy.

BOSTON — Sleep disturbances may be an important target for treating posttraumatic stress disorder, according to Dr. R. Bruce Lydiard of the Medical University of South Carolina in Charleston.

Persistent, severe posttraumatic nightmares, REM sleep fragmentation, insomnia, excessive nocturnal periodic limb movements, and sleep-disordered breathing are frequently experienced by individuals with PTSD, Dr. Lydiard said. Although these sleep problems are often viewed as secondary symptoms of PTSD, “the evidence suggests that after a traumatic event, sleep disruption appears before the onset of PTSD and may be a risk factor for it,” he proposed.

Polysomnographic data from 21 individuals with traumatic injuries showed that the number of REM periods and the (shorter) duration of REM periods within 1 month after the traumatic event were predictive of PTSD symptom severity 6 weeks later (Am. J. Psychiatry. 2002;159:1696–701).

Neurobiologically, the association makes sense, Dr. Lydiard said. “Sleep is regulated in part by brain areas in which PTSD-related changes occur,” which suggests that the stress response in PTSD and sleep dysfunction may be biologically linked.

Imaging studies suggest that exposure to trauma-related stimuli leads to hyperactivation in the amygdala and decreased activation in the medial prefrontal cortex/anterior cingulate cortex and hippocampus, with the magnitude of the activation correlating with the clinical severity of PTSD symptoms.

Polysomnographic investigations in patients with PTSD and sleep disturbances have revealed increased REM density, reduced REM duration, and increased motor activity, Dr. Lydiard said.

Together with clinical reports, “these data provide the basis for REM sleep dysregulation as a core feature in PTSD,” whereby increased activity in the amygdala and decreased inhibitory input from the medial prefrontal cortex lead to a persistently overactive noradrenergic system. “As a result, the usual rhythm of REM-NREM sleep is disrupted, and REM sleep is fragmented,” he said.

Based on this model, investigators have hypothesized that targeting noradrenergic signaling during or near REM episodes may normalize REM sleep, which in turn might improve PTSD sleep disturbances and, potentially, other PTSD symptoms, Dr. Lydiard said.

The alpha adrenergic antagonist prazosin has shown promise in multiple case and chart reviews, open-label trials, and placebo-controlled studies.

In one trial of 40 veterans with PTSD sleep disturbance, patients who were randomized to receive a nightly dose of prazosin — originally marketed as an antihypertensive agent — reported significant improvements in sleep quality and significant reductions in trauma nightmares, as well a better overall sense of well-being and improved daily functioning (Biol. Psychiatry 2007;61:928–34).

In another study, investigators evaluated the effect of prazosin vs. placebo on objective sleep parameters in 13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbance. The prazosin group experienced significantly increased total sleep time as well as increased REM sleep time and mean REM period duration (Biol. Psychiatry 2008;63:629–32).

In the various studies, the therapeutic benefit of prazosin was achieved within 1–2 weeks “with doses as low as 1 mg nightly,” Dr. Lydiard said.

In addition to improving sleep measures, prazosin may be useful for other trauma-related symptoms. In a small study of PTSD subjects whose nightmares were well controlled with the drug, the addition of small daytime doses lessened patients' reactivity to trauma cues during the day, he said (Biol. Psychiatry 2006;59:577–81). This finding “adds to the growing body of evidence that targeting sleep in PTSD is clinically relevant.”

Although some evidence exists to support the use of other antiadrenergic agents such as clonidine and guanfacine—as well as the anticonvulsant gabapentin—in PTSD, “large, randomized controlled trials are needed to clarify the role” of all of these agents, Dr. Lydiard said.

Additional studies also are warranted, he said, to investigate nonpharmacologic approaches to improving PTSD sleep disturbance, such as the use of imagery rehearsal therapy, which has demonstrated efficacy in small studies (J. Trauma. Stress 2009;22:236–9).

Dr. Lydiard disclosed receiving honoraria from Reed Medical Education, the logistics collaborator for the Massachusetts General Hospital Psychiatry Academy.

BOSTON — Sleep disturbances may be an important target for treating posttraumatic stress disorder, according to Dr. R. Bruce Lydiard of the Medical University of South Carolina in Charleston.

Persistent, severe posttraumatic nightmares, REM sleep fragmentation, insomnia, excessive nocturnal periodic limb movements, and sleep-disordered breathing are frequently experienced by individuals with PTSD, Dr. Lydiard said. Although these sleep problems are often viewed as secondary symptoms of PTSD, “the evidence suggests that after a traumatic event, sleep disruption appears before the onset of PTSD and may be a risk factor for it,” he proposed.

Polysomnographic data from 21 individuals with traumatic injuries showed that the number of REM periods and the (shorter) duration of REM periods within 1 month after the traumatic event were predictive of PTSD symptom severity 6 weeks later (Am. J. Psychiatry. 2002;159:1696–701).

Neurobiologically, the association makes sense, Dr. Lydiard said. “Sleep is regulated in part by brain areas in which PTSD-related changes occur,” which suggests that the stress response in PTSD and sleep dysfunction may be biologically linked.

Imaging studies suggest that exposure to trauma-related stimuli leads to hyperactivation in the amygdala and decreased activation in the medial prefrontal cortex/anterior cingulate cortex and hippocampus, with the magnitude of the activation correlating with the clinical severity of PTSD symptoms.

Polysomnographic investigations in patients with PTSD and sleep disturbances have revealed increased REM density, reduced REM duration, and increased motor activity, Dr. Lydiard said.

Together with clinical reports, “these data provide the basis for REM sleep dysregulation as a core feature in PTSD,” whereby increased activity in the amygdala and decreased inhibitory input from the medial prefrontal cortex lead to a persistently overactive noradrenergic system. “As a result, the usual rhythm of REM-NREM sleep is disrupted, and REM sleep is fragmented,” he said.

Based on this model, investigators have hypothesized that targeting noradrenergic signaling during or near REM episodes may normalize REM sleep, which in turn might improve PTSD sleep disturbances and, potentially, other PTSD symptoms, Dr. Lydiard said.

The alpha adrenergic antagonist prazosin has shown promise in multiple case and chart reviews, open-label trials, and placebo-controlled studies.

In one trial of 40 veterans with PTSD sleep disturbance, patients who were randomized to receive a nightly dose of prazosin — originally marketed as an antihypertensive agent — reported significant improvements in sleep quality and significant reductions in trauma nightmares, as well a better overall sense of well-being and improved daily functioning (Biol. Psychiatry 2007;61:928–34).

In another study, investigators evaluated the effect of prazosin vs. placebo on objective sleep parameters in 13 outpatients with chronic civilian trauma PTSD, frequent nightmares, and sleep disturbance. The prazosin group experienced significantly increased total sleep time as well as increased REM sleep time and mean REM period duration (Biol. Psychiatry 2008;63:629–32).

In the various studies, the therapeutic benefit of prazosin was achieved within 1–2 weeks “with doses as low as 1 mg nightly,” Dr. Lydiard said.

In addition to improving sleep measures, prazosin may be useful for other trauma-related symptoms. In a small study of PTSD subjects whose nightmares were well controlled with the drug, the addition of small daytime doses lessened patients' reactivity to trauma cues during the day, he said (Biol. Psychiatry 2006;59:577–81). This finding “adds to the growing body of evidence that targeting sleep in PTSD is clinically relevant.”

Although some evidence exists to support the use of other antiadrenergic agents such as clonidine and guanfacine—as well as the anticonvulsant gabapentin—in PTSD, “large, randomized controlled trials are needed to clarify the role” of all of these agents, Dr. Lydiard said.

Additional studies also are warranted, he said, to investigate nonpharmacologic approaches to improving PTSD sleep disturbance, such as the use of imagery rehearsal therapy, which has demonstrated efficacy in small studies (J. Trauma. Stress 2009;22:236–9).

Dr. Lydiard disclosed receiving honoraria from Reed Medical Education, the logistics collaborator for the Massachusetts General Hospital Psychiatry Academy.

Major Finding: Intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe C. difficile colitis who don't respond to standard treatment.

Data Source: Retrospective study of 15 patients treated with single-dose IVIG.

Disclosures: Dr. Yangco disclosed financial relationships with Sanofi Pasteur, Gilead Sciences, Pfizer, Tibotec, Merck, and J.G. Johnson.

BOSTON — Single-dose intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe, recurrent Clostridium difficile colitis that is refractory to standard treatment.

In a review of 15 patients whose C. difficile colitis was unresponsive to standard therapy with metronidazole, vancomycin, and/or other agents, adjunctive treatment with a single dose of intravenous immunoglobulin (IVIG) led to clinical improvement in 87% of the cases, reported lead investigator Dr. Bienvenido G. Yangco of the Infectious Disease Research Institute in Tampa.

“Thirteen of the 15 patients had improvement or resolution of diarrhea, fever, and leukocytosis and were eventually discharged from the hospital,” he said. “One patient who demonstrated initial improvement was readmitted to the hospital 1 month later for recurrent C. difficile colitis [CDC], while 10 of the remaining 11 patients who had a repeat C. difficile toxin test remained negative after IVIG and have maintained clinical improvement to date.”

The patients included in this review were treated between January 2009 and July 2010 and were C. difficile cytotoxin positive with diarrhea, abdominal pain, distention, fever, leukocytosis, radiographic or colonoscopic evidence of colitis, and persistent or recurrent clinical manifestations despite receiving metronidazole (12 patients), vancomycin (13 patients), nitazoxanide (13 patients), and probiotics (9 patients), Dr. Yangco explained. The patients' mean age was 77 years.

Of the 15 patients, 2 received a single IVIG dose of 200 mg/kg and 13 received a single 400-mg/kg dose. Among the patients receiving the higher dose, two underwent colectomy. One of these patients, whose colectomy was related to colorectal cancer, had resolution of CDC, and the other patient died, Dr. Yangco said. None of the patients had adverse effects from the IVIG treatment.

The findings are clinically relevant given the dramatic increases in the incidence and severity of C. difficile colitis in recent years and the suboptimal clinical outcomes observed with standard therapies, despite the relative nonexistence of C. difficile resistance to these drugs in vitro, said Dr. Yangco. He attributed the clinical/microbiological discrepancy to “low or waning antitoxin antibody levels in patients with C. difficile colitis.”

Although passive immunotherapy with IVIG in patients who don't respond to standard treatment has been used since 1991, and its efficacy has been reported in small case series and observational studies, no controlled trials of IVIG in CDC have been performed to date, said Dr. Yangco. “It should be noted that the IVIG doses in the published studies vary from 200 to 1,250 mg/kg for 1–5 consecutive days or once every 3 weeks for 2–3 doses, and in those reports there have been definite benefits and possible efficacy observed with IVIG,” he said. “None of the published studies” has discouraged its use.

Although the findings of the current study are limited by the small number of patients and the retrospective design, the apparent efficacy of single-dose IVIG for the treatment of severe, recurrent CDC “warrants further investigation in prospective, controlled studies,” Dr. Yangco stressed.

“It is very likely that [the] high cost of IVIG — often cited as an obstacle to its use — might be offset in these patients by the benefits associated with sustained clinical improvement, including shorter hospital stays and fewer readmissions.”

Major Finding: Intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe C. difficile colitis who don't respond to standard treatment.

Data Source: Retrospective study of 15 patients treated with single-dose IVIG.

Disclosures: Dr. Yangco disclosed financial relationships with Sanofi Pasteur, Gilead Sciences, Pfizer, Tibotec, Merck, and J.G. Johnson.

BOSTON — Single-dose intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe, recurrent Clostridium difficile colitis that is refractory to standard treatment.

In a review of 15 patients whose C. difficile colitis was unresponsive to standard therapy with metronidazole, vancomycin, and/or other agents, adjunctive treatment with a single dose of intravenous immunoglobulin (IVIG) led to clinical improvement in 87% of the cases, reported lead investigator Dr. Bienvenido G. Yangco of the Infectious Disease Research Institute in Tampa.

“Thirteen of the 15 patients had improvement or resolution of diarrhea, fever, and leukocytosis and were eventually discharged from the hospital,” he said. “One patient who demonstrated initial improvement was readmitted to the hospital 1 month later for recurrent C. difficile colitis [CDC], while 10 of the remaining 11 patients who had a repeat C. difficile toxin test remained negative after IVIG and have maintained clinical improvement to date.”

The patients included in this review were treated between January 2009 and July 2010 and were C. difficile cytotoxin positive with diarrhea, abdominal pain, distention, fever, leukocytosis, radiographic or colonoscopic evidence of colitis, and persistent or recurrent clinical manifestations despite receiving metronidazole (12 patients), vancomycin (13 patients), nitazoxanide (13 patients), and probiotics (9 patients), Dr. Yangco explained. The patients' mean age was 77 years.

Of the 15 patients, 2 received a single IVIG dose of 200 mg/kg and 13 received a single 400-mg/kg dose. Among the patients receiving the higher dose, two underwent colectomy. One of these patients, whose colectomy was related to colorectal cancer, had resolution of CDC, and the other patient died, Dr. Yangco said. None of the patients had adverse effects from the IVIG treatment.

The findings are clinically relevant given the dramatic increases in the incidence and severity of C. difficile colitis in recent years and the suboptimal clinical outcomes observed with standard therapies, despite the relative nonexistence of C. difficile resistance to these drugs in vitro, said Dr. Yangco. He attributed the clinical/microbiological discrepancy to “low or waning antitoxin antibody levels in patients with C. difficile colitis.”

Although passive immunotherapy with IVIG in patients who don't respond to standard treatment has been used since 1991, and its efficacy has been reported in small case series and observational studies, no controlled trials of IVIG in CDC have been performed to date, said Dr. Yangco. “It should be noted that the IVIG doses in the published studies vary from 200 to 1,250 mg/kg for 1–5 consecutive days or once every 3 weeks for 2–3 doses, and in those reports there have been definite benefits and possible efficacy observed with IVIG,” he said. “None of the published studies” has discouraged its use.

Although the findings of the current study are limited by the small number of patients and the retrospective design, the apparent efficacy of single-dose IVIG for the treatment of severe, recurrent CDC “warrants further investigation in prospective, controlled studies,” Dr. Yangco stressed.

“It is very likely that [the] high cost of IVIG — often cited as an obstacle to its use — might be offset in these patients by the benefits associated with sustained clinical improvement, including shorter hospital stays and fewer readmissions.”

Major Finding: Intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe C. difficile colitis who don't respond to standard treatment.

Data Source: Retrospective study of 15 patients treated with single-dose IVIG.

Disclosures: Dr. Yangco disclosed financial relationships with Sanofi Pasteur, Gilead Sciences, Pfizer, Tibotec, Merck, and J.G. Johnson.

BOSTON — Single-dose intravenous immunoglobulin may be an effective adjunctive therapy for patients with severe, recurrent Clostridium difficile colitis that is refractory to standard treatment.

In a review of 15 patients whose C. difficile colitis was unresponsive to standard therapy with metronidazole, vancomycin, and/or other agents, adjunctive treatment with a single dose of intravenous immunoglobulin (IVIG) led to clinical improvement in 87% of the cases, reported lead investigator Dr. Bienvenido G. Yangco of the Infectious Disease Research Institute in Tampa.

“Thirteen of the 15 patients had improvement or resolution of diarrhea, fever, and leukocytosis and were eventually discharged from the hospital,” he said. “One patient who demonstrated initial improvement was readmitted to the hospital 1 month later for recurrent C. difficile colitis [CDC], while 10 of the remaining 11 patients who had a repeat C. difficile toxin test remained negative after IVIG and have maintained clinical improvement to date.”

The patients included in this review were treated between January 2009 and July 2010 and were C. difficile cytotoxin positive with diarrhea, abdominal pain, distention, fever, leukocytosis, radiographic or colonoscopic evidence of colitis, and persistent or recurrent clinical manifestations despite receiving metronidazole (12 patients), vancomycin (13 patients), nitazoxanide (13 patients), and probiotics (9 patients), Dr. Yangco explained. The patients' mean age was 77 years.

Of the 15 patients, 2 received a single IVIG dose of 200 mg/kg and 13 received a single 400-mg/kg dose. Among the patients receiving the higher dose, two underwent colectomy. One of these patients, whose colectomy was related to colorectal cancer, had resolution of CDC, and the other patient died, Dr. Yangco said. None of the patients had adverse effects from the IVIG treatment.

The findings are clinically relevant given the dramatic increases in the incidence and severity of C. difficile colitis in recent years and the suboptimal clinical outcomes observed with standard therapies, despite the relative nonexistence of C. difficile resistance to these drugs in vitro, said Dr. Yangco. He attributed the clinical/microbiological discrepancy to “low or waning antitoxin antibody levels in patients with C. difficile colitis.”

Although passive immunotherapy with IVIG in patients who don't respond to standard treatment has been used since 1991, and its efficacy has been reported in small case series and observational studies, no controlled trials of IVIG in CDC have been performed to date, said Dr. Yangco. “It should be noted that the IVIG doses in the published studies vary from 200 to 1,250 mg/kg for 1–5 consecutive days or once every 3 weeks for 2–3 doses, and in those reports there have been definite benefits and possible efficacy observed with IVIG,” he said. “None of the published studies” has discouraged its use.

Although the findings of the current study are limited by the small number of patients and the retrospective design, the apparent efficacy of single-dose IVIG for the treatment of severe, recurrent CDC “warrants further investigation in prospective, controlled studies,” Dr. Yangco stressed.

“It is very likely that [the] high cost of IVIG — often cited as an obstacle to its use — might be offset in these patients by the benefits associated with sustained clinical improvement, including shorter hospital stays and fewer readmissions.”

DESTIN, FLA. – The benefits of tumor necrosis factor blockade extend beyond the joints to the hearts and minds of rheumatoid arthritis patients, Dr. Iain McInnes reported at the congress.

Findings from two studies suggest anti-TNF treatment can inhibit the cytokine-induced chain of events that leads to the increased risk of cardiovascular disease and clinical depression in RA.

Along with lead investigator Dr. Mike J.L. Peters of VU University Medical Center in Amsterdam, Dr. McInnes and colleagues at the University of Glasgow (Scotland) have shown, for the first time, that anti-TNF-alpha therapy lowers circulating levels of the cardiac neurohormone N-terminal prohormone brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis (RA) who do not have evident heart failure.

Previously identified as a clinically relevant biomarker for heart failure, NT-proBNP is independently associated with cardiovascular risk in individuals with and without preexisting cardiovascular disease. Thus, the observed reduction in NT-proBNP suggests a “potential beneficial effect of [TNF-alpha] blockers with respect to vascular risk and ventricular function in rheumatoid arthritis,” Dr. McInnes said.

The study measured serum NT-proBNP at baseline and after 16 weeks of biweekly adalimumab treatment in 171 consecutive RA patients without heart failure (Ann. Rheum. Dis. 2010 April 7 [doi:10.1136/ard.2009.119412]).

After week 16, the investigators observed an approximately 18% reduction in NT-proBNP levels, providing biological evidence that TNF-alpha blockade does not worsen ventricular function in patients with RA who do not have prevalent heart failure, and supporting epidemiologic findings that indicate it may reduce overall cardiovascular risks in these patients, said Dr. McInnes.

The results also add weight to the accumulating evidence that implicates TNF-alpha in the cardiovascular events associated with RA, and support the beneficial effect that blocking TNF-alpha has on surrogate vascular markers, he said.

In a separate study, Dr. McInnes and colleagues sought to assess the functional effects of anti-TNF-alpha therapy on the brains of depressed patients with RA, and determined that TNF-alpha blockade mediates altered serotonin transporter availability and induces an improvement in depression measures.

“This is critically important,” Dr. McInnes stressed. “I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients,” he said, referring to a 2006 report suggesting that the prevalence of major depressive disorder exceeds 40% and that of suicidal ideation is up to 11% in RA patients (Rheumatology [Oxford] 2006;45:1325-7).

Findings from earlier research have shown that proinflammatory cytokines can increase the density and activity of the serotonin transporter (SERT), a primary target for antidepressant therapy. On that basis, Dr. McInnes and his associates hypothesized that TNF blockade might be associated with altered SERT activity in RA patients, he said. They tested this hypothesis in a clinical, proof-of-concept study by measuring SERT density using SPECT (single-photon emission CT) in six patients with seropositive RA 2 weeks before the initiation of adalimumab therapy and 4 days after the last treatment, he said.

After anti-TNF-alpha therapy, “there was a significant decrease in the [SERT] density in all of the patients.” Along with that came overall improvements in physical and mental functioning, as measured by the Hamilton Rating Scale for Depression, the Social Functioning 36-item scale, the Hospital Anxiety and Depression Scale, and the composite 28 joint count Disease Activity Score, Dr. McInnes reported.

Although it is yet unclear whether the observed SERT alterations are specific to RA or are related to cytokine action in general, “the findings provide important insight into the biology linking clinical depression and rheumatoid arthritis.” If confirmed in larger studies, the findings may offer guidance for developing treatment strategies, according to Dr. McInnes.

Disclosures: Dr. McInnes has received research support or honoraria from Schering-Plough, Roche, Bristol-Myers Squibb Co., and Wyeth and has served as a consultant for Schering-Plough and Roche.

'I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients.'

Source DR. MCINNES

DESTIN, FLA. – The benefits of tumor necrosis factor blockade extend beyond the joints to the hearts and minds of rheumatoid arthritis patients, Dr. Iain McInnes reported at the congress.

Findings from two studies suggest anti-TNF treatment can inhibit the cytokine-induced chain of events that leads to the increased risk of cardiovascular disease and clinical depression in RA.

Along with lead investigator Dr. Mike J.L. Peters of VU University Medical Center in Amsterdam, Dr. McInnes and colleagues at the University of Glasgow (Scotland) have shown, for the first time, that anti-TNF-alpha therapy lowers circulating levels of the cardiac neurohormone N-terminal prohormone brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis (RA) who do not have evident heart failure.

Previously identified as a clinically relevant biomarker for heart failure, NT-proBNP is independently associated with cardiovascular risk in individuals with and without preexisting cardiovascular disease. Thus, the observed reduction in NT-proBNP suggests a “potential beneficial effect of [TNF-alpha] blockers with respect to vascular risk and ventricular function in rheumatoid arthritis,” Dr. McInnes said.

The study measured serum NT-proBNP at baseline and after 16 weeks of biweekly adalimumab treatment in 171 consecutive RA patients without heart failure (Ann. Rheum. Dis. 2010 April 7 [doi:10.1136/ard.2009.119412]).

After week 16, the investigators observed an approximately 18% reduction in NT-proBNP levels, providing biological evidence that TNF-alpha blockade does not worsen ventricular function in patients with RA who do not have prevalent heart failure, and supporting epidemiologic findings that indicate it may reduce overall cardiovascular risks in these patients, said Dr. McInnes.

The results also add weight to the accumulating evidence that implicates TNF-alpha in the cardiovascular events associated with RA, and support the beneficial effect that blocking TNF-alpha has on surrogate vascular markers, he said.

In a separate study, Dr. McInnes and colleagues sought to assess the functional effects of anti-TNF-alpha therapy on the brains of depressed patients with RA, and determined that TNF-alpha blockade mediates altered serotonin transporter availability and induces an improvement in depression measures.

“This is critically important,” Dr. McInnes stressed. “I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients,” he said, referring to a 2006 report suggesting that the prevalence of major depressive disorder exceeds 40% and that of suicidal ideation is up to 11% in RA patients (Rheumatology [Oxford] 2006;45:1325-7).

Findings from earlier research have shown that proinflammatory cytokines can increase the density and activity of the serotonin transporter (SERT), a primary target for antidepressant therapy. On that basis, Dr. McInnes and his associates hypothesized that TNF blockade might be associated with altered SERT activity in RA patients, he said. They tested this hypothesis in a clinical, proof-of-concept study by measuring SERT density using SPECT (single-photon emission CT) in six patients with seropositive RA 2 weeks before the initiation of adalimumab therapy and 4 days after the last treatment, he said.

After anti-TNF-alpha therapy, “there was a significant decrease in the [SERT] density in all of the patients.” Along with that came overall improvements in physical and mental functioning, as measured by the Hamilton Rating Scale for Depression, the Social Functioning 36-item scale, the Hospital Anxiety and Depression Scale, and the composite 28 joint count Disease Activity Score, Dr. McInnes reported.

Although it is yet unclear whether the observed SERT alterations are specific to RA or are related to cytokine action in general, “the findings provide important insight into the biology linking clinical depression and rheumatoid arthritis.” If confirmed in larger studies, the findings may offer guidance for developing treatment strategies, according to Dr. McInnes.

Disclosures: Dr. McInnes has received research support or honoraria from Schering-Plough, Roche, Bristol-Myers Squibb Co., and Wyeth and has served as a consultant for Schering-Plough and Roche.

'I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients.'

Source DR. MCINNES

DESTIN, FLA. – The benefits of tumor necrosis factor blockade extend beyond the joints to the hearts and minds of rheumatoid arthritis patients, Dr. Iain McInnes reported at the congress.

Findings from two studies suggest anti-TNF treatment can inhibit the cytokine-induced chain of events that leads to the increased risk of cardiovascular disease and clinical depression in RA.

Along with lead investigator Dr. Mike J.L. Peters of VU University Medical Center in Amsterdam, Dr. McInnes and colleagues at the University of Glasgow (Scotland) have shown, for the first time, that anti-TNF-alpha therapy lowers circulating levels of the cardiac neurohormone N-terminal prohormone brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis (RA) who do not have evident heart failure.

Previously identified as a clinically relevant biomarker for heart failure, NT-proBNP is independently associated with cardiovascular risk in individuals with and without preexisting cardiovascular disease. Thus, the observed reduction in NT-proBNP suggests a “potential beneficial effect of [TNF-alpha] blockers with respect to vascular risk and ventricular function in rheumatoid arthritis,” Dr. McInnes said.

The study measured serum NT-proBNP at baseline and after 16 weeks of biweekly adalimumab treatment in 171 consecutive RA patients without heart failure (Ann. Rheum. Dis. 2010 April 7 [doi:10.1136/ard.2009.119412]).

After week 16, the investigators observed an approximately 18% reduction in NT-proBNP levels, providing biological evidence that TNF-alpha blockade does not worsen ventricular function in patients with RA who do not have prevalent heart failure, and supporting epidemiologic findings that indicate it may reduce overall cardiovascular risks in these patients, said Dr. McInnes.

The results also add weight to the accumulating evidence that implicates TNF-alpha in the cardiovascular events associated with RA, and support the beneficial effect that blocking TNF-alpha has on surrogate vascular markers, he said.

In a separate study, Dr. McInnes and colleagues sought to assess the functional effects of anti-TNF-alpha therapy on the brains of depressed patients with RA, and determined that TNF-alpha blockade mediates altered serotonin transporter availability and induces an improvement in depression measures.

“This is critically important,” Dr. McInnes stressed. “I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients,” he said, referring to a 2006 report suggesting that the prevalence of major depressive disorder exceeds 40% and that of suicidal ideation is up to 11% in RA patients (Rheumatology [Oxford] 2006;45:1325-7).

Findings from earlier research have shown that proinflammatory cytokines can increase the density and activity of the serotonin transporter (SERT), a primary target for antidepressant therapy. On that basis, Dr. McInnes and his associates hypothesized that TNF blockade might be associated with altered SERT activity in RA patients, he said. They tested this hypothesis in a clinical, proof-of-concept study by measuring SERT density using SPECT (single-photon emission CT) in six patients with seropositive RA 2 weeks before the initiation of adalimumab therapy and 4 days after the last treatment, he said.

After anti-TNF-alpha therapy, “there was a significant decrease in the [SERT] density in all of the patients.” Along with that came overall improvements in physical and mental functioning, as measured by the Hamilton Rating Scale for Depression, the Social Functioning 36-item scale, the Hospital Anxiety and Depression Scale, and the composite 28 joint count Disease Activity Score, Dr. McInnes reported.

Although it is yet unclear whether the observed SERT alterations are specific to RA or are related to cytokine action in general, “the findings provide important insight into the biology linking clinical depression and rheumatoid arthritis.” If confirmed in larger studies, the findings may offer guidance for developing treatment strategies, according to Dr. McInnes.

Disclosures: Dr. McInnes has received research support or honoraria from Schering-Plough, Roche, Bristol-Myers Squibb Co., and Wyeth and has served as a consultant for Schering-Plough and Roche.

'I think we as rheumatologists underappreciate the prevalence and impact of depression on our patients.'

Source DR. MCINNES

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.

High systolic blood pressure, gait-balance deficiencies, and low self-reported health scores are linked to cognitive deficits in older adults with type 2 diabetes, according to a report in the September issue of Neuropsychology.

The three health-related covariates were associated with deficits in neurocognitive speed, executive functioning, and episodic memory in diabetic vs. nondiabetic adults, based on cross-sectional data from the Victoria Longitudinal Study (VLS), an ongoing, multicohort study comprising initially healthy community-dwelling adult volunteers from Western Canada. The study participants undergo cognitive, neuropsychological, health, and physiologic assessment at 3-year intervals.

The current analysis included 499 participants, aged 53-90 years, drawn from the study’s third independent sample. Excluded from the study were individuals who had been previously diagnosed with Alzheimer’s disease or vascular dementia, those scoring less than 26 on the Mini-Mental Status Examination, and those with clusters of potential comorbid neurologic, cardiovascular, and psychiatric diseases (Neuropsychology 2010;24:547-62).

Type 2 diabetes was present in 41 participants who were compared with the remaining 458 participants without diabetes. The two groups were similar in age, education, and gender proportions, as well as marital and dwelling status, and no group differences were found for global cognition or visual or audio acuity, according to C. Peggy McFall of the University of Alberta, Edmonton, and colleagues.

The investigators identified from the literature 13 health-related potential covariates and identified relationships between the covariates and type 2 diabetes. Six potential covariates – systolic blood pressure, body mass index, gait-balance, depression, negative affect, and subjective health, were found to be sensitive to type 2 diabetes associations with performance on seven cognitive measures. These measures were episodic memory, the Stroop Test, the Hayling Sentence Completion Test, the Color Trials Test 2, semantic speed, reaction time, and the Digit Symbol Substitution Test.

In the regression analyses, systolic blood pressure, gait-balance, and subjective health were found to mediate multiple cognitive outcomes. For example, systolic blood pressure attenuated the type 2 diabetes–cognition relationship by 30%-50% for episodic memory, neurocognitive speed, and executive function. As such, systolic blood pressure may be associated with type 2 diabetes related vascular disturbance.

The gait-balance composite mediated type 2 diabetes cognition relationships for all seven cognitive measures, with attenuation effects ranging from 32% to 62%, the authors reported. The substantial influence of this composite might reflect the impact of diabetes on specific neural mechanisms associated with gait and balance or, more broadly, it might affect the “multiple overlapping areas [of the brain] associated with gait-balance and cognition.”

The subjective health composite accounted for 35%-50% of performance on five different cognitive tests. “Specifically, [type 2 diabetes] may exacerbate levels of psychosocial stress, depression, and (lower) health self efficacy – all of which may negatively affect motivation for performance on cognitive tests,” the authors wrote. Further, with diabetes, “processes of interoception may detect inner biological stimuli of discomfort or nutritional deficits that could be associated with lower subjective health ratings and, by extension, cognitive performance.”

The findings point to the need for “neuropsychological research on neural bases of [diabetes-related] cognitive decline, clinical research on intervention and treatment strategies, and larger-scale longitudinal epidemiological studies, all of which will help clarify the multilateral (and possibly dynamic) relationships and mechanisms of [type 2 diabetes], related comorbidities, and cognitive outcomes,” the authors concluded.

The authors reported no financial disclosures. The study was supported by a grant from the National Institutes of Health.