Mary Ann Moon

The dopaminergic stabilizing drug pridopidine showed signs of improving motor function without worsening chorea in patients with Huntington’s disease, despite failing to meet its primary end point in an industry-sponsored phase III trial.

The drug also failed to improve nonmotor outcomes for both secondary and tertiary end points that measured cognitive and functional deficits, Dr. Justo Garcia de Yebenes of the department of neurology, Hospital Ramón y Cajal, Madrid, and his associates reported online Nov. 7 in the Lancet Neurology.

However, the higher of the two doses of pridopidine that the investigators tested in this international trial produced significant improvement in the tertiary end point of total motor score in the Unified Huntington's Disease Rating Scale (UHDRS), they noted.*

Pridopidine belongs to a new class of drugs known as dopaminergic stabilizers, which act primarily at dopamine type 2 receptors. In vivo studies have shown that the drug "normalizes dysregulated psychomotor functions while having only subtle effects on normal psychomotor activity." In animal models, it has been reported to improve signs of depression, anxiety, and motor dysfunction.

Dr. Garcia de Yebenes and his colleagues performed the MermaiHD trial (Multinational European Multicentre ACR16 Study in Huntington’s Disease) to explore pridopidine’s usefulness in treating symptoms of Huntington’s disease. The double-blind trial involved 437 ambulatory patients recruited from 32 clinics in Austria, Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom.

The study subjects were randomly assigned to receive 45 mg oral pridopidine (148 patients), 90 mg pridopidine (145 patients), or matching placebo (144 patients) daily for 26 weeks. They were allowed to take concomitant therapies including antidepressants and other psychotropic drugs as long as they had been receiving a stable dose of those agents for at least 6 weeks before randomization.

The primary outcome measure was improvement in a shortened version of the total motor score on the UHDRS, which was assessed at baseline and weeks 4, 8, 12, and 26. This modified score addressed dysarthria, tongue protrusion, finger tapping, pronate and supinate hands, fist-hand-palm sequencing, arm rigidity, body bradykinesia, gait, tandem walking, and retropulsion pulling. It did not assess eye movements, dystonia, or chorea.

The mean age of all patients in the study was nearly 51 years, and it had been an average of nearly 5 years since they had been diagnosed with Huntington’s disease.

At baseline, the mean modified motor score was 18-20 points in the three study groups. At week 26, that had decreased in the 90-mg group (–0.99 points) relative to the placebo group, but not to a significant degree. However, in a per-protocol analysis, the decline in mean modified motor score (–1.29 points) was significant relative to placebo, the investigators wrote (Lancet 2011 Nov. 7 [doi: 10.1016/S1474-4422(11)70233-2]).*

There were no significant differences between either dose of pridopidine and placebo in any of the secondary outcomes, which included improvement in clinical global impression-improvement scores, total UHDRS scores, and anxiety and depression scores.

A single tertiary outcome – mean change in UHDRS total motor score – was significantly better in the 90-mg pridopidine group than in the placebo group. Patients who took the 90-mg dose had a mean score that was 2.93 points lower than the score for placebo-treated patients; the baseline UHDRS total motor score was 41-43 points. This difference in scores was attributed to improvements in change was primarily because of improvements in eye movements, dystonia, hand movements, and gait and balance, but not chorea.*

"Pridopidine was well tolerated and had an adverse event profile similar to that of placebo," the researchers wrote.

Overall, 38% of the low-dose group, 44% of the high-dose group, and 45% of the placebo group reported adverse events judged to be related to the study drug. The rates of serious adverse events were 7%, 6%, and 8%, respectively.

Although these results "fell short of" success, the improvements in UHDRS total motor score "have been reproduced in a phase IIb trial run in parallel with our study," and may warrant further investigation, Dr. Garcia de Yebenes and his colleagues wrote.

This study was funded by NeuroSearch A/S, a European biopharmaceutical company that makes pridopidine and other CNS drugs. Dr. Garcia de Yebenes reported receiving institutional funding from NeuroSearch, and several of his coauthors are employees of NeuroSearch. Other colleagues reported receiving payments for services to NeuroSearch and payments or research support from numerous industry sources, foundations, research networks, and patient advocacy groups.

* Corrections, 11/15/2011: An earlier version of this article misstated the statistical significance of items in the trial's tertiary endpoint, the total motor score in the UHDRS. It also misstated the mean difference in scores at week 26 between the group taking 90 mg pridopidine and the placebo group on the primary end point of the mean modified motor score and the tertiary end point of the total motor score in the UHDRS.

The dopaminergic stabilizing drug pridopidine showed signs of improving motor function without worsening chorea in patients with Huntington’s disease, despite failing to meet its primary end point in an industry-sponsored phase III trial.

The drug also failed to improve nonmotor outcomes for both secondary and tertiary end points that measured cognitive and functional deficits, Dr. Justo Garcia de Yebenes of the department of neurology, Hospital Ramón y Cajal, Madrid, and his associates reported online Nov. 7 in the Lancet Neurology.

However, the higher of the two doses of pridopidine that the investigators tested in this international trial produced significant improvement in the tertiary end point of total motor score in the Unified Huntington's Disease Rating Scale (UHDRS), they noted.*

Pridopidine belongs to a new class of drugs known as dopaminergic stabilizers, which act primarily at dopamine type 2 receptors. In vivo studies have shown that the drug "normalizes dysregulated psychomotor functions while having only subtle effects on normal psychomotor activity." In animal models, it has been reported to improve signs of depression, anxiety, and motor dysfunction.

Dr. Garcia de Yebenes and his colleagues performed the MermaiHD trial (Multinational European Multicentre ACR16 Study in Huntington’s Disease) to explore pridopidine’s usefulness in treating symptoms of Huntington’s disease. The double-blind trial involved 437 ambulatory patients recruited from 32 clinics in Austria, Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom.

The study subjects were randomly assigned to receive 45 mg oral pridopidine (148 patients), 90 mg pridopidine (145 patients), or matching placebo (144 patients) daily for 26 weeks. They were allowed to take concomitant therapies including antidepressants and other psychotropic drugs as long as they had been receiving a stable dose of those agents for at least 6 weeks before randomization.

The primary outcome measure was improvement in a shortened version of the total motor score on the UHDRS, which was assessed at baseline and weeks 4, 8, 12, and 26. This modified score addressed dysarthria, tongue protrusion, finger tapping, pronate and supinate hands, fist-hand-palm sequencing, arm rigidity, body bradykinesia, gait, tandem walking, and retropulsion pulling. It did not assess eye movements, dystonia, or chorea.

The mean age of all patients in the study was nearly 51 years, and it had been an average of nearly 5 years since they had been diagnosed with Huntington’s disease.

At baseline, the mean modified motor score was 18-20 points in the three study groups. At week 26, that had decreased in the 90-mg group (–0.99 points) relative to the placebo group, but not to a significant degree. However, in a per-protocol analysis, the decline in mean modified motor score (–1.29 points) was significant relative to placebo, the investigators wrote (Lancet 2011 Nov. 7 [doi: 10.1016/S1474-4422(11)70233-2]).*

There were no significant differences between either dose of pridopidine and placebo in any of the secondary outcomes, which included improvement in clinical global impression-improvement scores, total UHDRS scores, and anxiety and depression scores.

A single tertiary outcome – mean change in UHDRS total motor score – was significantly better in the 90-mg pridopidine group than in the placebo group. Patients who took the 90-mg dose had a mean score that was 2.93 points lower than the score for placebo-treated patients; the baseline UHDRS total motor score was 41-43 points. This difference in scores was attributed to improvements in change was primarily because of improvements in eye movements, dystonia, hand movements, and gait and balance, but not chorea.*

"Pridopidine was well tolerated and had an adverse event profile similar to that of placebo," the researchers wrote.

Overall, 38% of the low-dose group, 44% of the high-dose group, and 45% of the placebo group reported adverse events judged to be related to the study drug. The rates of serious adverse events were 7%, 6%, and 8%, respectively.

Although these results "fell short of" success, the improvements in UHDRS total motor score "have been reproduced in a phase IIb trial run in parallel with our study," and may warrant further investigation, Dr. Garcia de Yebenes and his colleagues wrote.

This study was funded by NeuroSearch A/S, a European biopharmaceutical company that makes pridopidine and other CNS drugs. Dr. Garcia de Yebenes reported receiving institutional funding from NeuroSearch, and several of his coauthors are employees of NeuroSearch. Other colleagues reported receiving payments for services to NeuroSearch and payments or research support from numerous industry sources, foundations, research networks, and patient advocacy groups.

* Corrections, 11/15/2011: An earlier version of this article misstated the statistical significance of items in the trial's tertiary endpoint, the total motor score in the UHDRS. It also misstated the mean difference in scores at week 26 between the group taking 90 mg pridopidine and the placebo group on the primary end point of the mean modified motor score and the tertiary end point of the total motor score in the UHDRS.

The dopaminergic stabilizing drug pridopidine showed signs of improving motor function without worsening chorea in patients with Huntington’s disease, despite failing to meet its primary end point in an industry-sponsored phase III trial.

The drug also failed to improve nonmotor outcomes for both secondary and tertiary end points that measured cognitive and functional deficits, Dr. Justo Garcia de Yebenes of the department of neurology, Hospital Ramón y Cajal, Madrid, and his associates reported online Nov. 7 in the Lancet Neurology.

However, the higher of the two doses of pridopidine that the investigators tested in this international trial produced significant improvement in the tertiary end point of total motor score in the Unified Huntington's Disease Rating Scale (UHDRS), they noted.*

Pridopidine belongs to a new class of drugs known as dopaminergic stabilizers, which act primarily at dopamine type 2 receptors. In vivo studies have shown that the drug "normalizes dysregulated psychomotor functions while having only subtle effects on normal psychomotor activity." In animal models, it has been reported to improve signs of depression, anxiety, and motor dysfunction.

Dr. Garcia de Yebenes and his colleagues performed the MermaiHD trial (Multinational European Multicentre ACR16 Study in Huntington’s Disease) to explore pridopidine’s usefulness in treating symptoms of Huntington’s disease. The double-blind trial involved 437 ambulatory patients recruited from 32 clinics in Austria, Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom.

The study subjects were randomly assigned to receive 45 mg oral pridopidine (148 patients), 90 mg pridopidine (145 patients), or matching placebo (144 patients) daily for 26 weeks. They were allowed to take concomitant therapies including antidepressants and other psychotropic drugs as long as they had been receiving a stable dose of those agents for at least 6 weeks before randomization.

The primary outcome measure was improvement in a shortened version of the total motor score on the UHDRS, which was assessed at baseline and weeks 4, 8, 12, and 26. This modified score addressed dysarthria, tongue protrusion, finger tapping, pronate and supinate hands, fist-hand-palm sequencing, arm rigidity, body bradykinesia, gait, tandem walking, and retropulsion pulling. It did not assess eye movements, dystonia, or chorea.

The mean age of all patients in the study was nearly 51 years, and it had been an average of nearly 5 years since they had been diagnosed with Huntington’s disease.

At baseline, the mean modified motor score was 18-20 points in the three study groups. At week 26, that had decreased in the 90-mg group (–0.99 points) relative to the placebo group, but not to a significant degree. However, in a per-protocol analysis, the decline in mean modified motor score (–1.29 points) was significant relative to placebo, the investigators wrote (Lancet 2011 Nov. 7 [doi: 10.1016/S1474-4422(11)70233-2]).*

There were no significant differences between either dose of pridopidine and placebo in any of the secondary outcomes, which included improvement in clinical global impression-improvement scores, total UHDRS scores, and anxiety and depression scores.

A single tertiary outcome – mean change in UHDRS total motor score – was significantly better in the 90-mg pridopidine group than in the placebo group. Patients who took the 90-mg dose had a mean score that was 2.93 points lower than the score for placebo-treated patients; the baseline UHDRS total motor score was 41-43 points. This difference in scores was attributed to improvements in change was primarily because of improvements in eye movements, dystonia, hand movements, and gait and balance, but not chorea.*

"Pridopidine was well tolerated and had an adverse event profile similar to that of placebo," the researchers wrote.

Overall, 38% of the low-dose group, 44% of the high-dose group, and 45% of the placebo group reported adverse events judged to be related to the study drug. The rates of serious adverse events were 7%, 6%, and 8%, respectively.

Although these results "fell short of" success, the improvements in UHDRS total motor score "have been reproduced in a phase IIb trial run in parallel with our study," and may warrant further investigation, Dr. Garcia de Yebenes and his colleagues wrote.

This study was funded by NeuroSearch A/S, a European biopharmaceutical company that makes pridopidine and other CNS drugs. Dr. Garcia de Yebenes reported receiving institutional funding from NeuroSearch, and several of his coauthors are employees of NeuroSearch. Other colleagues reported receiving payments for services to NeuroSearch and payments or research support from numerous industry sources, foundations, research networks, and patient advocacy groups.

* Corrections, 11/15/2011: An earlier version of this article misstated the statistical significance of items in the trial's tertiary endpoint, the total motor score in the UHDRS. It also misstated the mean difference in scores at week 26 between the group taking 90 mg pridopidine and the placebo group on the primary end point of the mean modified motor score and the tertiary end point of the total motor score in the UHDRS.

A pediatric office–based intervention for assessing and treating children’s mental health problems significantly reduced oppositional behavior, inattention, hyperactivity, and functional impairment in a study of 78 children reported online Nov. 7 in the Archives of Pediatrics and Adolescent Medicine.

The availability of mental health services at a pediatrician’s office greatly increased the number of patients who initiated treatment and the number who completed treatment, consistent with previous reports that parents and children are more accepting of visits to a pediatric setting than to a mental health setting, said David J. Kolko, Ph.D., and his associates.

The authors reported the results of a 2-year pilot study comparing this doctor-office collaborative care (DOCC) program with "enhanced" usual care in four large community-based pediatric practices affiliated with the Children’s Hospital of Pittsburgh. A total of 29 pediatricians participated.

In the DOCC intervention, three master’s-degree–level staff members (a social worker, a counselor, and a nurse) served as case managers and worked under the supervision of a senior clinician who had input from a child and adolescent psychiatrist. The case managers provided on-site and telephone services to patients and parents: they conducted psychological assessments, explained diagnoses and treatment recommendations, provided education on behavioral disorders, gave parents and children skills training in cognitive behavior treatment, provided peer and school consultation as needed, and coordinated any necessary medical care such as drug therapy.

"Most parent skills-training content targeted the management of family stressors and child behavior, whereas child skills training primarily targeted affect regulation and social skills," noted Dr. Kolko of Western Psychiatric Institute and Clinic, Oakland, Pa., and the departments of psychiatry, psychology, and pediatrics at the University of Pittsburgh, and his colleagues.

The case managers met with the pediatricians and the entire care team weekly to review the cases. Their sessions with patients and families were videotaped so that they could be reviewed by supervising clinicians as well as the participating pediatricians.

An "enhanced usual care" intervention was provided for comparison (control group). In it, the case managers provided education about the child’s mental or behavioral disorder(s), explained clinical recommendations, and gave up to three referral options for a mental health provider tailored to the child’s needs, geographic location, and insurance. They also made a single follow-up phone call 2 weeks later to check on the patient’s progress.

The pediatricians referred to the study any children aged 5-12 years who seemed appropriate for formal screening for mental health problems. A total of 78 patients met study inclusion criteria (rated at or above the 75th percentile on the externalizing problems subscale of the Pediatric Symptom Checklist) and agreed to participate. The most common psychiatric diagnoses were anxiety disorder (47% of children), ADHD (45%), and opposition defiance disorder (49%).

The children were randomly assigned to the DOCC program (55 patients) or enhanced usual care (23 patients). After 6 months, their scores on a battery of measures were compared with scores obtained at baseline. In addition to the Pediatric Symptom Checklist, these measures included the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, the Clinical Global Impressions (CGI) Scale, the Vanderbilt ADHD Parent Rating Scale, and the Screen for Child Anxiety Related Emotional Disorders.

All 55 of the children in the DOCC group received some mental health treatment, compared with only 4 of the 23 in the control group. Similarly, 43 children in the DOCC group, compared with none in the usual care group, completed their treatment. The use of recommended ADHD medication was higher in the DOCC group (78% of eligible patients) than in the control group (20%), but that difference was not significant because of the small sample size of the control group.

Children in the DOCC group were more likely to be rated as improved or significantly improved (66%) at the conclusion of the program than were those in the usual care group (8%). In particular, CGI scores showed markedly greater improvement for the DOCC group (62%) than the control group (0%), the investigators said (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.201]).

The DOCC intervention was superior to usual care in reducing oppositional behavior, inattention, hyperactivity, and functional impairment. However, there were no differences between the two groups regarding improvement in anxiety or depression.

On average, the case managers spent approximately 2 hours per child conducting screening and assessments, 14 hours providing services, and another 2-3 hours on administrative tasks including consulting with the pediatricians. Pediatricians spent approximately 1 hour per child providing direct services and 18 minutes in consultations with case managers, other staff, and physician supervisors.

A total of 24 of the participating pediatricians provided feedback on their experience with the program. Overall, they were highly supportive, acknowledged the importance of providing on-site services, reported that they "considered themselves unable to provide mental health care in a competent or effective way on their own," and expressed great enthusiasm for the training they received and for collaborating with a case manager when treating behavioral problems.

Parents also reported strong preferences for receiving mental health services at the pediatrician’s office.

This pilot study was limited in that it had a "modest" sample size and lacked follow-up of longer than 6 months, so the effectiveness of the DOCC model "requires replication in a more rigorous trial," Dr. Kolko and his associates said.

For such a model to be fully integrated into primary care practices, several key issues must be addressed, including the use of office space, scheduling, staff training and credentialing, sharing of medical records, and financial reimbursement, they added.

This study was supported by the National Institute of Mental Health. No financial conflicts of interest were reported.

A pediatric office–based intervention for assessing and treating children’s mental health problems significantly reduced oppositional behavior, inattention, hyperactivity, and functional impairment in a study of 78 children reported online Nov. 7 in the Archives of Pediatrics and Adolescent Medicine.

The availability of mental health services at a pediatrician’s office greatly increased the number of patients who initiated treatment and the number who completed treatment, consistent with previous reports that parents and children are more accepting of visits to a pediatric setting than to a mental health setting, said David J. Kolko, Ph.D., and his associates.

The authors reported the results of a 2-year pilot study comparing this doctor-office collaborative care (DOCC) program with "enhanced" usual care in four large community-based pediatric practices affiliated with the Children’s Hospital of Pittsburgh. A total of 29 pediatricians participated.

In the DOCC intervention, three master’s-degree–level staff members (a social worker, a counselor, and a nurse) served as case managers and worked under the supervision of a senior clinician who had input from a child and adolescent psychiatrist. The case managers provided on-site and telephone services to patients and parents: they conducted psychological assessments, explained diagnoses and treatment recommendations, provided education on behavioral disorders, gave parents and children skills training in cognitive behavior treatment, provided peer and school consultation as needed, and coordinated any necessary medical care such as drug therapy.

"Most parent skills-training content targeted the management of family stressors and child behavior, whereas child skills training primarily targeted affect regulation and social skills," noted Dr. Kolko of Western Psychiatric Institute and Clinic, Oakland, Pa., and the departments of psychiatry, psychology, and pediatrics at the University of Pittsburgh, and his colleagues.

The case managers met with the pediatricians and the entire care team weekly to review the cases. Their sessions with patients and families were videotaped so that they could be reviewed by supervising clinicians as well as the participating pediatricians.

An "enhanced usual care" intervention was provided for comparison (control group). In it, the case managers provided education about the child’s mental or behavioral disorder(s), explained clinical recommendations, and gave up to three referral options for a mental health provider tailored to the child’s needs, geographic location, and insurance. They also made a single follow-up phone call 2 weeks later to check on the patient’s progress.

The pediatricians referred to the study any children aged 5-12 years who seemed appropriate for formal screening for mental health problems. A total of 78 patients met study inclusion criteria (rated at or above the 75th percentile on the externalizing problems subscale of the Pediatric Symptom Checklist) and agreed to participate. The most common psychiatric diagnoses were anxiety disorder (47% of children), ADHD (45%), and opposition defiance disorder (49%).

The children were randomly assigned to the DOCC program (55 patients) or enhanced usual care (23 patients). After 6 months, their scores on a battery of measures were compared with scores obtained at baseline. In addition to the Pediatric Symptom Checklist, these measures included the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, the Clinical Global Impressions (CGI) Scale, the Vanderbilt ADHD Parent Rating Scale, and the Screen for Child Anxiety Related Emotional Disorders.

All 55 of the children in the DOCC group received some mental health treatment, compared with only 4 of the 23 in the control group. Similarly, 43 children in the DOCC group, compared with none in the usual care group, completed their treatment. The use of recommended ADHD medication was higher in the DOCC group (78% of eligible patients) than in the control group (20%), but that difference was not significant because of the small sample size of the control group.

Children in the DOCC group were more likely to be rated as improved or significantly improved (66%) at the conclusion of the program than were those in the usual care group (8%). In particular, CGI scores showed markedly greater improvement for the DOCC group (62%) than the control group (0%), the investigators said (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.201]).

The DOCC intervention was superior to usual care in reducing oppositional behavior, inattention, hyperactivity, and functional impairment. However, there were no differences between the two groups regarding improvement in anxiety or depression.

On average, the case managers spent approximately 2 hours per child conducting screening and assessments, 14 hours providing services, and another 2-3 hours on administrative tasks including consulting with the pediatricians. Pediatricians spent approximately 1 hour per child providing direct services and 18 minutes in consultations with case managers, other staff, and physician supervisors.

A total of 24 of the participating pediatricians provided feedback on their experience with the program. Overall, they were highly supportive, acknowledged the importance of providing on-site services, reported that they "considered themselves unable to provide mental health care in a competent or effective way on their own," and expressed great enthusiasm for the training they received and for collaborating with a case manager when treating behavioral problems.

Parents also reported strong preferences for receiving mental health services at the pediatrician’s office.

This pilot study was limited in that it had a "modest" sample size and lacked follow-up of longer than 6 months, so the effectiveness of the DOCC model "requires replication in a more rigorous trial," Dr. Kolko and his associates said.

For such a model to be fully integrated into primary care practices, several key issues must be addressed, including the use of office space, scheduling, staff training and credentialing, sharing of medical records, and financial reimbursement, they added.

This study was supported by the National Institute of Mental Health. No financial conflicts of interest were reported.

A pediatric office–based intervention for assessing and treating children’s mental health problems significantly reduced oppositional behavior, inattention, hyperactivity, and functional impairment in a study of 78 children reported online Nov. 7 in the Archives of Pediatrics and Adolescent Medicine.

The availability of mental health services at a pediatrician’s office greatly increased the number of patients who initiated treatment and the number who completed treatment, consistent with previous reports that parents and children are more accepting of visits to a pediatric setting than to a mental health setting, said David J. Kolko, Ph.D., and his associates.

The authors reported the results of a 2-year pilot study comparing this doctor-office collaborative care (DOCC) program with "enhanced" usual care in four large community-based pediatric practices affiliated with the Children’s Hospital of Pittsburgh. A total of 29 pediatricians participated.

In the DOCC intervention, three master’s-degree–level staff members (a social worker, a counselor, and a nurse) served as case managers and worked under the supervision of a senior clinician who had input from a child and adolescent psychiatrist. The case managers provided on-site and telephone services to patients and parents: they conducted psychological assessments, explained diagnoses and treatment recommendations, provided education on behavioral disorders, gave parents and children skills training in cognitive behavior treatment, provided peer and school consultation as needed, and coordinated any necessary medical care such as drug therapy.

"Most parent skills-training content targeted the management of family stressors and child behavior, whereas child skills training primarily targeted affect regulation and social skills," noted Dr. Kolko of Western Psychiatric Institute and Clinic, Oakland, Pa., and the departments of psychiatry, psychology, and pediatrics at the University of Pittsburgh, and his colleagues.

The case managers met with the pediatricians and the entire care team weekly to review the cases. Their sessions with patients and families were videotaped so that they could be reviewed by supervising clinicians as well as the participating pediatricians.

An "enhanced usual care" intervention was provided for comparison (control group). In it, the case managers provided education about the child’s mental or behavioral disorder(s), explained clinical recommendations, and gave up to three referral options for a mental health provider tailored to the child’s needs, geographic location, and insurance. They also made a single follow-up phone call 2 weeks later to check on the patient’s progress.

The pediatricians referred to the study any children aged 5-12 years who seemed appropriate for formal screening for mental health problems. A total of 78 patients met study inclusion criteria (rated at or above the 75th percentile on the externalizing problems subscale of the Pediatric Symptom Checklist) and agreed to participate. The most common psychiatric diagnoses were anxiety disorder (47% of children), ADHD (45%), and opposition defiance disorder (49%).

The children were randomly assigned to the DOCC program (55 patients) or enhanced usual care (23 patients). After 6 months, their scores on a battery of measures were compared with scores obtained at baseline. In addition to the Pediatric Symptom Checklist, these measures included the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, the Clinical Global Impressions (CGI) Scale, the Vanderbilt ADHD Parent Rating Scale, and the Screen for Child Anxiety Related Emotional Disorders.

All 55 of the children in the DOCC group received some mental health treatment, compared with only 4 of the 23 in the control group. Similarly, 43 children in the DOCC group, compared with none in the usual care group, completed their treatment. The use of recommended ADHD medication was higher in the DOCC group (78% of eligible patients) than in the control group (20%), but that difference was not significant because of the small sample size of the control group.

Children in the DOCC group were more likely to be rated as improved or significantly improved (66%) at the conclusion of the program than were those in the usual care group (8%). In particular, CGI scores showed markedly greater improvement for the DOCC group (62%) than the control group (0%), the investigators said (Arch. Pediatr. Adolesc. Med. 2011 Nov. 7 [doi:10.1001/archpediatrics.2011.201]).

The DOCC intervention was superior to usual care in reducing oppositional behavior, inattention, hyperactivity, and functional impairment. However, there were no differences between the two groups regarding improvement in anxiety or depression.

On average, the case managers spent approximately 2 hours per child conducting screening and assessments, 14 hours providing services, and another 2-3 hours on administrative tasks including consulting with the pediatricians. Pediatricians spent approximately 1 hour per child providing direct services and 18 minutes in consultations with case managers, other staff, and physician supervisors.

A total of 24 of the participating pediatricians provided feedback on their experience with the program. Overall, they were highly supportive, acknowledged the importance of providing on-site services, reported that they "considered themselves unable to provide mental health care in a competent or effective way on their own," and expressed great enthusiasm for the training they received and for collaborating with a case manager when treating behavioral problems.

Parents also reported strong preferences for receiving mental health services at the pediatrician’s office.

This pilot study was limited in that it had a "modest" sample size and lacked follow-up of longer than 6 months, so the effectiveness of the DOCC model "requires replication in a more rigorous trial," Dr. Kolko and his associates said.

For such a model to be fully integrated into primary care practices, several key issues must be addressed, including the use of office space, scheduling, staff training and credentialing, sharing of medical records, and financial reimbursement, they added.

This study was supported by the National Institute of Mental Health. No financial conflicts of interest were reported.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

Robust predictive biomarkers of response to rheumatoid arthritis treatment remain elusive, researchers said in a review of the recent literature on this topic, which was published online Oct. 28 in Annals of the Rheumatic Diseases.

The ability to identify those rheumatoid arthritis (RA) therapies to which a patient is likely to respond is crucial in order to prevent unnecessary exposure to toxic adverse effects and allow physicians to "abandon the trial-and-error approach to treatment in favor of evidence-based guidance."

It would also help control treatment costs, said Dr. Paul Emery, who is the arthritis research campaign professor of rheumatology and head of the academic section of musculoskeletal disease at the University of Leeds (England), and Dr. Thomas Dörner, who is professor of rheumatology at Charité Universitätsmedizin Berlin.

They assessed the recent literature for evidence supporting the use of various biomarkers in this regard. These fell into four categories: genetic, protein, and cellular biomarkers, as well as predictive patient factors.

Genetic markers show the most promise as indicators of RA treatment response, but studies have been limited to date, and better-designed research is needed to confirm their potential usefulness.

For example, several polymorphisms of the tumor necrosis factor (TNF)–alpha gene have been studied, but the results have been inconsistent. Some studies have suggested that certain polymorphisms predict the response to TNF inhibitors such as etanercept, adalimumab, and infliximab, but others have contradicted this finding.

"There may be some merit in further investigation of the [single nucleotide polymorphism] in the TNF-308 promoter region to confirm its potential" to predict response to TNF inhibitors, but so far "the data are not conclusive because studies ... have been limited by the small patient numbers, heterogeneity in the underlying genetic background, [and] differences in study design," Dr. Emery and Dr. Dörner said (Ann. Rheum. Dis. 2011 Oct. 28 [doi:10.1136/ard.2010.148015]).

Some investigators have suggested that some major histocompatibility complex alleles that confer susceptibility to RA, such as the shared epitope in the human leukocyte antigen region, may be potential markers of treatment response. But overall, findings from studies thus far "indicate that the [shared epitope] motif is not a robust genetic marker for predicting response to TNF inhibitors."

The findings have been similarly sparse for other gene polymorphisms such as the p38 network of mitogen-activated protein kinases and variations in the PTPN22, STAT4, TRAF1-C5, PADI4, and CTLA-4 genes. Current data are too limited to determine whether markers for these genes might predict treatment response.

Analyzing mRNA expression of thousands of genes simultaneously is emerging as a promising technique to identify unique sets of genes that are expressed differently between responders and nonresponders to a given therapy. However, there have been few studies of this method, and some of those few analyzed samples from the peripheral blood before it became known that samples from the synovial fluid are more useful.

On another front, several proteins involved in cartilage turnover, bone resorption, or the TNF-signaling pathway have been proposed as possible markers of treatment response, particularly to anti-TNF agents. But the research to date has involved very small numbers of subjects. "Consequently, no robust protein biomarkers have yet been confirmed as predicting response," the investigators said.

Similarly, it may be possible in the future to use the dominant type of interferon signature in a patient’s peripheral blood sample to predict response to rituximab in particular, but this hasn’t yet been confirmed in multiple studies.

And several autoantibodies present in blood samples from RA patients may eventually move to "the forefront of RA management, although we are not quite there," Dr. Emery and Dr. Dörner added.

With regard to cellular biomarkers, certain subsets of B cells have been noted during either depletion or repletion phases of treatment. "However, the utility of assessing B cells before and during treatment requires confirmation by independent controlled studies and rigorous validation before [it] can be recommended for use in clinical practice," the researchers said.

Finally, both clinical and demographic patient traits have been proposed as predictive of treatment response, including the baseline 28-joint disease activity score and C-reactive protein levels. But none has proved to be sufficiently predictive to guide therapy, they said.

The writing of this review was supported in part by Hoffmann-La Roche. Dr. Emery reported ties to Pfizer, Abbott, Bristol-Myers Squibb, Merck, Novartis, and Roche. Dr. Dörner reported ties to Chugai, Roche, and UCB.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients reported in the Nov. 3 issue of the New England Journal of Medicine.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries. The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used "coaches" to improve patients’ understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such "substantial financial liability" that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects). All the patients were "quite sick," requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs "had little success" in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program. "The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries," they noted.

In addition, "the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status." The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show "it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program," Dr. McCall and Dr. Cromwell said.

The results also "suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention," they added.

This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients reported in the Nov. 3 issue of the New England Journal of Medicine.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries. The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used "coaches" to improve patients’ understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such "substantial financial liability" that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects). All the patients were "quite sick," requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs "had little success" in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program. "The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries," they noted.

In addition, "the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status." The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show "it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program," Dr. McCall and Dr. Cromwell said.

The results also "suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention," they added.

This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients reported in the Nov. 3 issue of the New England Journal of Medicine.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries. The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used "coaches" to improve patients’ understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such "substantial financial liability" that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects). All the patients were "quite sick," requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs "had little success" in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program. "The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries," they noted.

In addition, "the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status." The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show "it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program," Dr. McCall and Dr. Cromwell said.

The results also "suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention," they added.

This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Health care–associated Clostridium difficile infection correlates with different host and pathogen variables than does health care–associated C. difficile colonization, according to a report in the Nov. 3 issue of the New England Journal of Medicine.

These findings "add to the understanding of C. difficile infection and colonization, and have implications for prevention and therapy," said Dr. Vivian G. Loo of McGill University Health Centre, Montreal, and her associates.

Patients who develop C. difficile infection during hospitalization are likely to be older, to have a history of recent antibiotic use, to be taking proton pump inhibitors, and to carry the NAP1 strain of the organism.

In contrast, patients who show gut colonization with C. difficile but no infection during hospitalization are likely to have been hospitalized during the preceding 2 months, to have a recent history of chemotherapy, to be taking H₂ blockers or PPIs, and to carry antibodies against toxin B.

The link to previous hospitalization "suggests previous exposure to C. difficile and possibly the subsequent development of immunity," whereas the link to chemotherapy, H₂ blockers, and PPIs suggests that disruption of the bowel flora allowed for C. difficile colonization, Dr. Loo and her associates said.

Dr. Loo and associates examined host risk factors for C. difficile in 4,143 consecutive adults who were admitted to six university-affiliated hospitals in Canada during a recent 6-month period. The one hepatobiliary, eight general medicine, and five general surgery units from which patients were recruited for the study were chosen because they historically had either very high or very low rates of C. difficile infection.

The study subjects provided rectal swabs or stool samples cultured for toxigenic C. difficile upon admission, once a week during their hospitalization, at the onset of diarrhea (in the cases in which diarrhea developed), and at hospital discharge. They also were contacted 60 days after hospital discharge to determine whether diarrhea developed during that time.

For the assessment of antibody levels, subjects also provided serum samples at admission.

A total of 184 patients (4.4%) had asymptomatic colonization at admission. Another 117 (2.8%) developed the infection during hospitalization, and 123 (3.0%) developed asymptomatic C. difficile colonization during hospitalization.

The incidence of health care–associated C. difficile infection was 28.1 cases per 10,000 patient-days, and that of health care–associated C. difficile colonization was 29.5 per 10,000 patient-days.

There were 14 deaths within 60 days of C. difficile infection diagnosis, for a crude mortality of 12.0%. Death was attributed directly to C. difficile infection in two cases (1.7%), and the infection was considered a contributing cause of death in another six cases (5.1%).

C. difficile infection necessitated intensive care in one patient, but no patients required colectomy. Of the 117 infected patients, 29 developed at least one recurrence during the 60-day follow-up.

Older age was particularly significantly associated with C. difficile infection. For every year of age older than 18, the risk of health care–associated C. difficile infection rose by approximately 2%, the investigators said (N. Engl. J. Med. 2011;365:1693-703).

This study was supported by the Consortium de Recherche sur le Clostridium difficile. Dr. Loo reported receiving consulting fees from Merck, and her associates reported ties to Pfizer, Spartan Biosciences, Cubist Pharmaceuticals, Cepheid, and Genome Canada.

Health care–associated Clostridium difficile infection correlates with different host and pathogen variables than does health care–associated C. difficile colonization, according to a report in the Nov. 3 issue of the New England Journal of Medicine.

These findings "add to the understanding of C. difficile infection and colonization, and have implications for prevention and therapy," said Dr. Vivian G. Loo of McGill University Health Centre, Montreal, and her associates.

Patients who develop C. difficile infection during hospitalization are likely to be older, to have a history of recent antibiotic use, to be taking proton pump inhibitors, and to carry the NAP1 strain of the organism.

In contrast, patients who show gut colonization with C. difficile but no infection during hospitalization are likely to have been hospitalized during the preceding 2 months, to have a recent history of chemotherapy, to be taking H₂ blockers or PPIs, and to carry antibodies against toxin B.

The link to previous hospitalization "suggests previous exposure to C. difficile and possibly the subsequent development of immunity," whereas the link to chemotherapy, H₂ blockers, and PPIs suggests that disruption of the bowel flora allowed for C. difficile colonization, Dr. Loo and her associates said.

Dr. Loo and associates examined host risk factors for C. difficile in 4,143 consecutive adults who were admitted to six university-affiliated hospitals in Canada during a recent 6-month period. The one hepatobiliary, eight general medicine, and five general surgery units from which patients were recruited for the study were chosen because they historically had either very high or very low rates of C. difficile infection.

The study subjects provided rectal swabs or stool samples cultured for toxigenic C. difficile upon admission, once a week during their hospitalization, at the onset of diarrhea (in the cases in which diarrhea developed), and at hospital discharge. They also were contacted 60 days after hospital discharge to determine whether diarrhea developed during that time.

For the assessment of antibody levels, subjects also provided serum samples at admission.

A total of 184 patients (4.4%) had asymptomatic colonization at admission. Another 117 (2.8%) developed the infection during hospitalization, and 123 (3.0%) developed asymptomatic C. difficile colonization during hospitalization.

The incidence of health care–associated C. difficile infection was 28.1 cases per 10,000 patient-days, and that of health care–associated C. difficile colonization was 29.5 per 10,000 patient-days.

There were 14 deaths within 60 days of C. difficile infection diagnosis, for a crude mortality of 12.0%. Death was attributed directly to C. difficile infection in two cases (1.7%), and the infection was considered a contributing cause of death in another six cases (5.1%).

C. difficile infection necessitated intensive care in one patient, but no patients required colectomy. Of the 117 infected patients, 29 developed at least one recurrence during the 60-day follow-up.

Older age was particularly significantly associated with C. difficile infection. For every year of age older than 18, the risk of health care–associated C. difficile infection rose by approximately 2%, the investigators said (N. Engl. J. Med. 2011;365:1693-703).

This study was supported by the Consortium de Recherche sur le Clostridium difficile. Dr. Loo reported receiving consulting fees from Merck, and her associates reported ties to Pfizer, Spartan Biosciences, Cubist Pharmaceuticals, Cepheid, and Genome Canada.

Health care–associated Clostridium difficile infection correlates with different host and pathogen variables than does health care–associated C. difficile colonization, according to a report in the Nov. 3 issue of the New England Journal of Medicine.

These findings "add to the understanding of C. difficile infection and colonization, and have implications for prevention and therapy," said Dr. Vivian G. Loo of McGill University Health Centre, Montreal, and her associates.

Patients who develop C. difficile infection during hospitalization are likely to be older, to have a history of recent antibiotic use, to be taking proton pump inhibitors, and to carry the NAP1 strain of the organism.

In contrast, patients who show gut colonization with C. difficile but no infection during hospitalization are likely to have been hospitalized during the preceding 2 months, to have a recent history of chemotherapy, to be taking H₂ blockers or PPIs, and to carry antibodies against toxin B.

The link to previous hospitalization "suggests previous exposure to C. difficile and possibly the subsequent development of immunity," whereas the link to chemotherapy, H₂ blockers, and PPIs suggests that disruption of the bowel flora allowed for C. difficile colonization, Dr. Loo and her associates said.

Dr. Loo and associates examined host risk factors for C. difficile in 4,143 consecutive adults who were admitted to six university-affiliated hospitals in Canada during a recent 6-month period. The one hepatobiliary, eight general medicine, and five general surgery units from which patients were recruited for the study were chosen because they historically had either very high or very low rates of C. difficile infection.

The study subjects provided rectal swabs or stool samples cultured for toxigenic C. difficile upon admission, once a week during their hospitalization, at the onset of diarrhea (in the cases in which diarrhea developed), and at hospital discharge. They also were contacted 60 days after hospital discharge to determine whether diarrhea developed during that time.

For the assessment of antibody levels, subjects also provided serum samples at admission.

A total of 184 patients (4.4%) had asymptomatic colonization at admission. Another 117 (2.8%) developed the infection during hospitalization, and 123 (3.0%) developed asymptomatic C. difficile colonization during hospitalization.

The incidence of health care–associated C. difficile infection was 28.1 cases per 10,000 patient-days, and that of health care–associated C. difficile colonization was 29.5 per 10,000 patient-days.

There were 14 deaths within 60 days of C. difficile infection diagnosis, for a crude mortality of 12.0%. Death was attributed directly to C. difficile infection in two cases (1.7%), and the infection was considered a contributing cause of death in another six cases (5.1%).

C. difficile infection necessitated intensive care in one patient, but no patients required colectomy. Of the 117 infected patients, 29 developed at least one recurrence during the 60-day follow-up.

Older age was particularly significantly associated with C. difficile infection. For every year of age older than 18, the risk of health care–associated C. difficile infection rose by approximately 2%, the investigators said (N. Engl. J. Med. 2011;365:1693-703).

This study was supported by the Consortium de Recherche sur le Clostridium difficile. Dr. Loo reported receiving consulting fees from Merck, and her associates reported ties to Pfizer, Spartan Biosciences, Cubist Pharmaceuticals, Cepheid, and Genome Canada.

Even low levels of alcohol consumption – as little as 3-6 glasses of wine per week – increase the risk of developing breast cancer, according to a report in the Nov. 2 issue of JAMA.

"Prior studies have consistently demonstrated a linear dose-response relationship between alcohol consumption and breast cancer risk, with an increased risk mainly observed among women who consumed the equivalent of at least one alcoholic beverage daily, but power was limited at the lower levels of alcohol consumption to determine whether there was a lower threshold. Our data demonstrate that even consumption of alcohol as low as 5-9.9 g per day ... may be associated with a modest increase in risk," said Dr. Wendy Y. Chen of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her associates.

They analyzed data from the Nurses’ Health Study to assess the role of alcohol in breast cancer risk. The NHS involved female registered nurses who were aged 30-55 years at the study’s inception in 1976. The nurses were sent follow-up questionnaires every 2 years to update risk factor information and the development of disease. The study population was predominantly white (93.7% white, 2% black, 0.7% Asian, and 3.6% other or unknown ethnicity).

For this study, Dr. Chen and her colleagues analyzed data beginning in 1980, when alcohol intake was first assessed, and ending in 2008. The 74,854 subjects provided information on both their past and current drinking patterns.

A total of 7,690 cases of invasive breast cancer were diagnosed in these subjects during the study period.

Compared with women who did not drink alcohol, those who drank even a small amount showed a modestly but significantly increased risk of breast cancer, with a relative risk of 1.15. The risk rose as alcohol consumption increased, so women who drank at least 30 g of alcohol daily (the equivalent of two drinks per day) had a relative risk of 1.51.

"We observed a 10% increase in risk with each 10 g per day of alcohol intake," the investigators said (JAMA 2011;306:1884-90).

Both drinking during young adulthood and drinking later in life were independently associated with breast cancer risk, and the cumulative average alcohol consumption over a long period of time was the measure that had the strongest correlation. This highlights the importance of the totality of a woman’s exposure to alcohol throughout her lifetime rather than during a specific period, the researchers noted.

"We did not find any difference by type of alcoholic beverage (i.e., beer, wine, or liquor)," they added.

The tumor’s estrogen-receptor status also did not influence the association between alcohol intake and breast cancer risk, and neither did ductal or lobular histology.

The exact mechanism by which alcohol raises breast cancer risk is not yet known, but it is "probable" that its effect on circulating estrogen levels plays a role. Alcohol could raise these levels in both premenopausal and postmenopausal women by increasing aromatase activity, decreasing hepatic catabolism of androgens, or affecting adrenal steroid production. It may also increase breast tissue’s sensitivity to estrogens, Dr. Chen and her associates said.

The study was limited in that subjects were predominantly white. However, "the limited available data suggest that the association between alcohol use and breast cancer does not differ by ethnicity," they noted.

Given the study findings, every patient "will need to weigh the modest risk of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption."

This study was supported by the National Institutes of Health. Dr. Chen and her associates did not report any relevant financial disclosures.

Even low levels of alcohol consumption – as little as 3-6 glasses of wine per week – increase the risk of developing breast cancer, according to a report in the Nov. 2 issue of JAMA.

"Prior studies have consistently demonstrated a linear dose-response relationship between alcohol consumption and breast cancer risk, with an increased risk mainly observed among women who consumed the equivalent of at least one alcoholic beverage daily, but power was limited at the lower levels of alcohol consumption to determine whether there was a lower threshold. Our data demonstrate that even consumption of alcohol as low as 5-9.9 g per day ... may be associated with a modest increase in risk," said Dr. Wendy Y. Chen of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her associates.

They analyzed data from the Nurses’ Health Study to assess the role of alcohol in breast cancer risk. The NHS involved female registered nurses who were aged 30-55 years at the study’s inception in 1976. The nurses were sent follow-up questionnaires every 2 years to update risk factor information and the development of disease. The study population was predominantly white (93.7% white, 2% black, 0.7% Asian, and 3.6% other or unknown ethnicity).

For this study, Dr. Chen and her colleagues analyzed data beginning in 1980, when alcohol intake was first assessed, and ending in 2008. The 74,854 subjects provided information on both their past and current drinking patterns.

A total of 7,690 cases of invasive breast cancer were diagnosed in these subjects during the study period.

Compared with women who did not drink alcohol, those who drank even a small amount showed a modestly but significantly increased risk of breast cancer, with a relative risk of 1.15. The risk rose as alcohol consumption increased, so women who drank at least 30 g of alcohol daily (the equivalent of two drinks per day) had a relative risk of 1.51.

"We observed a 10% increase in risk with each 10 g per day of alcohol intake," the investigators said (JAMA 2011;306:1884-90).

Both drinking during young adulthood and drinking later in life were independently associated with breast cancer risk, and the cumulative average alcohol consumption over a long period of time was the measure that had the strongest correlation. This highlights the importance of the totality of a woman’s exposure to alcohol throughout her lifetime rather than during a specific period, the researchers noted.

"We did not find any difference by type of alcoholic beverage (i.e., beer, wine, or liquor)," they added.

The tumor’s estrogen-receptor status also did not influence the association between alcohol intake and breast cancer risk, and neither did ductal or lobular histology.

The exact mechanism by which alcohol raises breast cancer risk is not yet known, but it is "probable" that its effect on circulating estrogen levels plays a role. Alcohol could raise these levels in both premenopausal and postmenopausal women by increasing aromatase activity, decreasing hepatic catabolism of androgens, or affecting adrenal steroid production. It may also increase breast tissue’s sensitivity to estrogens, Dr. Chen and her associates said.

The study was limited in that subjects were predominantly white. However, "the limited available data suggest that the association between alcohol use and breast cancer does not differ by ethnicity," they noted.

Given the study findings, every patient "will need to weigh the modest risk of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption."

This study was supported by the National Institutes of Health. Dr. Chen and her associates did not report any relevant financial disclosures.

Even low levels of alcohol consumption – as little as 3-6 glasses of wine per week – increase the risk of developing breast cancer, according to a report in the Nov. 2 issue of JAMA.

"Prior studies have consistently demonstrated a linear dose-response relationship between alcohol consumption and breast cancer risk, with an increased risk mainly observed among women who consumed the equivalent of at least one alcoholic beverage daily, but power was limited at the lower levels of alcohol consumption to determine whether there was a lower threshold. Our data demonstrate that even consumption of alcohol as low as 5-9.9 g per day ... may be associated with a modest increase in risk," said Dr. Wendy Y. Chen of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her associates.

They analyzed data from the Nurses’ Health Study to assess the role of alcohol in breast cancer risk. The NHS involved female registered nurses who were aged 30-55 years at the study’s inception in 1976. The nurses were sent follow-up questionnaires every 2 years to update risk factor information and the development of disease. The study population was predominantly white (93.7% white, 2% black, 0.7% Asian, and 3.6% other or unknown ethnicity).

For this study, Dr. Chen and her colleagues analyzed data beginning in 1980, when alcohol intake was first assessed, and ending in 2008. The 74,854 subjects provided information on both their past and current drinking patterns.

A total of 7,690 cases of invasive breast cancer were diagnosed in these subjects during the study period.

Compared with women who did not drink alcohol, those who drank even a small amount showed a modestly but significantly increased risk of breast cancer, with a relative risk of 1.15. The risk rose as alcohol consumption increased, so women who drank at least 30 g of alcohol daily (the equivalent of two drinks per day) had a relative risk of 1.51.

"We observed a 10% increase in risk with each 10 g per day of alcohol intake," the investigators said (JAMA 2011;306:1884-90).

Both drinking during young adulthood and drinking later in life were independently associated with breast cancer risk, and the cumulative average alcohol consumption over a long period of time was the measure that had the strongest correlation. This highlights the importance of the totality of a woman’s exposure to alcohol throughout her lifetime rather than during a specific period, the researchers noted.

"We did not find any difference by type of alcoholic beverage (i.e., beer, wine, or liquor)," they added.

The tumor’s estrogen-receptor status also did not influence the association between alcohol intake and breast cancer risk, and neither did ductal or lobular histology.

The exact mechanism by which alcohol raises breast cancer risk is not yet known, but it is "probable" that its effect on circulating estrogen levels plays a role. Alcohol could raise these levels in both premenopausal and postmenopausal women by increasing aromatase activity, decreasing hepatic catabolism of androgens, or affecting adrenal steroid production. It may also increase breast tissue’s sensitivity to estrogens, Dr. Chen and her associates said.

The study was limited in that subjects were predominantly white. However, "the limited available data suggest that the association between alcohol use and breast cancer does not differ by ethnicity," they noted.

Given the study findings, every patient "will need to weigh the modest risk of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption."

This study was supported by the National Institutes of Health. Dr. Chen and her associates did not report any relevant financial disclosures.

Interleukin-5 appears to play an important role in the accumulation of eosinophils in pediatric eosinophilic esophagitis, because treatment with the anti-IL-5 monoclonal antibody mepolizumab reduced the mean eosinophil count in 89% of children, Dr. Amal H. Assa’ad and her colleagues reported in the November issue of Gastroenterology.

In this double-blind, randomized, prospective trial of mepolizumab in children aged 2-17 years, the reduction in eosinophil count became evident within 4 weeks after the conclusion of therapy. The effect persisted for another 16 weeks, but to a lesser extent (Gastroenterology 2011 November [doi: 10.1053/j.gastro.2011.07.044]).

The etiologic role of IL-5 has been established in animal models of eosinophilic esophagitis (EE), and mepolizumab has been found effective in adults with several eosinophilic disorders, including eosinophilic dermatitis, eczema, asthma, and EE.

The authors assessed the efficacy and safety of three monthly intravenous infusions of the drug in 57 children who had isolated EE that was unresponsive to standard dietary and steroid therapies. Three doses were used: minimal (0.55 mg/kg), low (2.5 mg/kg), and high (10 mg/kg). The 0.55-mg/kg dose "was expected to be minimally efficacious" and served as a comparator. It was considered unethical to have a placebo group because all participants had to undergo multiple biopsies under general anesthesia.

Biopsies were obtained during endoscopy at baseline, week 12, and week 24 from the distal and middle esophagus, as well as areas where macroscopic changes such as white plaques were noted, said Dr. Assa’ad of Cincinnati Children’s Hospital Medical Center, and her colleagues.

The primary efficacy end point was the proportion of patients with a complete response, defined as a peak esophageal intraepithelial eosinophil count of less than 5 per high-powered field (hpf) at week 12. Five of 57 patients (9%) achieved this end point.

Overall, the peak eosinophil count decreased from 123 per hpf at baseline to 40 per hpf at week 12. It rose to 82 per hpf at week 24 – still lower than baseline. Similarly, the overall mean eosinophil count was 39 per hpf at baseline, 9 per hpf at week 12, and 23 per hpf at week 24.

At 12 weeks, 18 patients (32%) had peak intraepithelial eosinophil counts less than 20 per hpf, and 51 (89%) had mean intraepithelial eosinophil counts of less than 20 per hpf.

Treatment response did not consistently correlate with the dose of mepolizumab, which indicates that lower doses may be therapeutic, they added.

"Of all the esophageal histopathologic abnormalities present at baseline, eosinophil microabscesses and eosinophil aggregations resolved in most patients at week 12, and remained mostly resolved at week 24. [In contrast,] basal zone hyperplasia and increased papillae length showed a low rate of resolution."

The authors performed a post hoc analysis to identify factors that might predict treatment response. The only factor found to predict a complete response to mepolizumab was a higher baseline eosinophil count, whereas age, sex, race, body mass index, age at onset of EE, disease duration, previous therapies, and symptoms were not predictive.

Patients’ symptoms were less frequent after mepolizumab therapy, but not to a significant degree. This may be because patients had minimal symptoms at baseline, which limited the capacity to show clinically relevant improvement.

There were no hypersensitivity reactions to the drug, no dose-related trends in adverse event rates, and no clinically relevant changes in vital signs, laboratory results, or ECG. GI adverse events were common but were likely related to the underlying disorder, the investigators said. They concluded that the safety of this monoclonal antibody was demonstrated for the first time in children.

This study was sponsored by GlaxoSmithKline; employees of the company contributed to the study design and collection, analysis, and interpretation of data. Dr. Assa’ad’s associates also reported ties to Cephalon, Meritage Pharmaceuticals, and Sunovion.

Interleukin-5 appears to play an important role in the accumulation of eosinophils in pediatric eosinophilic esophagitis, because treatment with the anti-IL-5 monoclonal antibody mepolizumab reduced the mean eosinophil count in 89% of children, Dr. Amal H. Assa’ad and her colleagues reported in the November issue of Gastroenterology.

In this double-blind, randomized, prospective trial of mepolizumab in children aged 2-17 years, the reduction in eosinophil count became evident within 4 weeks after the conclusion of therapy. The effect persisted for another 16 weeks, but to a lesser extent (Gastroenterology 2011 November [doi: 10.1053/j.gastro.2011.07.044]).

The etiologic role of IL-5 has been established in animal models of eosinophilic esophagitis (EE), and mepolizumab has been found effective in adults with several eosinophilic disorders, including eosinophilic dermatitis, eczema, asthma, and EE.

The authors assessed the efficacy and safety of three monthly intravenous infusions of the drug in 57 children who had isolated EE that was unresponsive to standard dietary and steroid therapies. Three doses were used: minimal (0.55 mg/kg), low (2.5 mg/kg), and high (10 mg/kg). The 0.55-mg/kg dose "was expected to be minimally efficacious" and served as a comparator. It was considered unethical to have a placebo group because all participants had to undergo multiple biopsies under general anesthesia.

Biopsies were obtained during endoscopy at baseline, week 12, and week 24 from the distal and middle esophagus, as well as areas where macroscopic changes such as white plaques were noted, said Dr. Assa’ad of Cincinnati Children’s Hospital Medical Center, and her colleagues.

The primary efficacy end point was the proportion of patients with a complete response, defined as a peak esophageal intraepithelial eosinophil count of less than 5 per high-powered field (hpf) at week 12. Five of 57 patients (9%) achieved this end point.

Overall, the peak eosinophil count decreased from 123 per hpf at baseline to 40 per hpf at week 12. It rose to 82 per hpf at week 24 – still lower than baseline. Similarly, the overall mean eosinophil count was 39 per hpf at baseline, 9 per hpf at week 12, and 23 per hpf at week 24.

At 12 weeks, 18 patients (32%) had peak intraepithelial eosinophil counts less than 20 per hpf, and 51 (89%) had mean intraepithelial eosinophil counts of less than 20 per hpf.

Treatment response did not consistently correlate with the dose of mepolizumab, which indicates that lower doses may be therapeutic, they added.

"Of all the esophageal histopathologic abnormalities present at baseline, eosinophil microabscesses and eosinophil aggregations resolved in most patients at week 12, and remained mostly resolved at week 24. [In contrast,] basal zone hyperplasia and increased papillae length showed a low rate of resolution."

The authors performed a post hoc analysis to identify factors that might predict treatment response. The only factor found to predict a complete response to mepolizumab was a higher baseline eosinophil count, whereas age, sex, race, body mass index, age at onset of EE, disease duration, previous therapies, and symptoms were not predictive.

Patients’ symptoms were less frequent after mepolizumab therapy, but not to a significant degree. This may be because patients had minimal symptoms at baseline, which limited the capacity to show clinically relevant improvement.

There were no hypersensitivity reactions to the drug, no dose-related trends in adverse event rates, and no clinically relevant changes in vital signs, laboratory results, or ECG. GI adverse events were common but were likely related to the underlying disorder, the investigators said. They concluded that the safety of this monoclonal antibody was demonstrated for the first time in children.

This study was sponsored by GlaxoSmithKline; employees of the company contributed to the study design and collection, analysis, and interpretation of data. Dr. Assa’ad’s associates also reported ties to Cephalon, Meritage Pharmaceuticals, and Sunovion.

Interleukin-5 appears to play an important role in the accumulation of eosinophils in pediatric eosinophilic esophagitis, because treatment with the anti-IL-5 monoclonal antibody mepolizumab reduced the mean eosinophil count in 89% of children, Dr. Amal H. Assa’ad and her colleagues reported in the November issue of Gastroenterology.

In this double-blind, randomized, prospective trial of mepolizumab in children aged 2-17 years, the reduction in eosinophil count became evident within 4 weeks after the conclusion of therapy. The effect persisted for another 16 weeks, but to a lesser extent (Gastroenterology 2011 November [doi: 10.1053/j.gastro.2011.07.044]).

The etiologic role of IL-5 has been established in animal models of eosinophilic esophagitis (EE), and mepolizumab has been found effective in adults with several eosinophilic disorders, including eosinophilic dermatitis, eczema, asthma, and EE.

The authors assessed the efficacy and safety of three monthly intravenous infusions of the drug in 57 children who had isolated EE that was unresponsive to standard dietary and steroid therapies. Three doses were used: minimal (0.55 mg/kg), low (2.5 mg/kg), and high (10 mg/kg). The 0.55-mg/kg dose "was expected to be minimally efficacious" and served as a comparator. It was considered unethical to have a placebo group because all participants had to undergo multiple biopsies under general anesthesia.

Biopsies were obtained during endoscopy at baseline, week 12, and week 24 from the distal and middle esophagus, as well as areas where macroscopic changes such as white plaques were noted, said Dr. Assa’ad of Cincinnati Children’s Hospital Medical Center, and her colleagues.

The primary efficacy end point was the proportion of patients with a complete response, defined as a peak esophageal intraepithelial eosinophil count of less than 5 per high-powered field (hpf) at week 12. Five of 57 patients (9%) achieved this end point.

Overall, the peak eosinophil count decreased from 123 per hpf at baseline to 40 per hpf at week 12. It rose to 82 per hpf at week 24 – still lower than baseline. Similarly, the overall mean eosinophil count was 39 per hpf at baseline, 9 per hpf at week 12, and 23 per hpf at week 24.

At 12 weeks, 18 patients (32%) had peak intraepithelial eosinophil counts less than 20 per hpf, and 51 (89%) had mean intraepithelial eosinophil counts of less than 20 per hpf.

Treatment response did not consistently correlate with the dose of mepolizumab, which indicates that lower doses may be therapeutic, they added.

"Of all the esophageal histopathologic abnormalities present at baseline, eosinophil microabscesses and eosinophil aggregations resolved in most patients at week 12, and remained mostly resolved at week 24. [In contrast,] basal zone hyperplasia and increased papillae length showed a low rate of resolution."

The authors performed a post hoc analysis to identify factors that might predict treatment response. The only factor found to predict a complete response to mepolizumab was a higher baseline eosinophil count, whereas age, sex, race, body mass index, age at onset of EE, disease duration, previous therapies, and symptoms were not predictive.

Patients’ symptoms were less frequent after mepolizumab therapy, but not to a significant degree. This may be because patients had minimal symptoms at baseline, which limited the capacity to show clinically relevant improvement.

There were no hypersensitivity reactions to the drug, no dose-related trends in adverse event rates, and no clinically relevant changes in vital signs, laboratory results, or ECG. GI adverse events were common but were likely related to the underlying disorder, the investigators said. They concluded that the safety of this monoclonal antibody was demonstrated for the first time in children.

This study was sponsored by GlaxoSmithKline; employees of the company contributed to the study design and collection, analysis, and interpretation of data. Dr. Assa’ad’s associates also reported ties to Cephalon, Meritage Pharmaceuticals, and Sunovion.

The incidence of acute pancreatitis did not rise during or immediately after "the world’s largest beer fair," Oktoberfest in Munich, even though an estimated 6.6 million liters of beer were consumed there in only 16 days, Dr. Veit Phillip and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This unexpected result indicates that "acute attacks of alcoholic pancreatitis seem to be associated with long-term, heavy alcohol exposure rather than short-term, excessive alcohol drinking," the investigators wrote (Clin. Gastroenterol. Hepatol. 2011 [doi: 10.1016/j.cgh.2011.07.022]).

©Dan Race/Fotolia.com

Noting that "little is known about the impact of short-term aggravation of alcohol consumption on the incidence of pancreatitis," Dr. Phillip and his associates assessed the affects of Oktoberfest by studying consecutive patients admitted to 27 of the 31 hospitals in the Munich area with acute pancreatitis during the celebration and during two control periods in 2008.

The more than 6 million L of beer imbibed between Sept. 20 and Oct. 5 at Oktoberfest that year contained 340 million g pure alcohol. Hospital admissions for acute pancreatitis from Sept. 20 through Oct. 7 were compared with those from the 18-day interval immediately preceding the study period and the 18-day interval immediately following it. Each period included 6 weekend days.

A total of 91% of the admitted patients were permanent residents of the Munich area rather than visitors. A total of 188 patients were admitted for acute pancreatitis during all 54 days of observation, for an overall incidence of 42.8/100,000 person-years.

This rate is 117% higher than the rate reported for another region of Germany in an earlier study. "Because our data are the first to be analyzed from this population, we do not know if there has been an increase [in acute pancreatitis] over the last few years," or if the discrepancy is due to different drinking habits between the two regions, said Dr. Phillip of Technische Universität München and his colleagues.

The incidence of acute pancreatitis admissions was not significantly different between Oktoberfest (42.3/100,000 person-years) and the two control periods (43.0/100,000 person-years).

In fact, slightly more cases developed during the first control period (37.2% of all cases) than during Oktoberfest (33.0%) or the second control period (29.8%). This may be because the first control period coincided with the end of the summer holidays in that region, the researchers said.

Alcohol was listed as the most common etiology for acute pancreatitis (36.7% of cases), including 15 cases of acute alcohol-induced attacks in patients who had longstanding chronic pancreatitis. A biliary etiology also was common (34.6% of cases).

Less common were post-ERCP [endoscopic retrograde cholangiopancreatography] pancreatitis (3.2%) and postsurgical pancreatitis (2.7%). Drug toxicity was cited as the etiology in 4.3% of cases, and was attributed to NSAIDs (four cases), azathioprine (two cases), 5-aminosalicylic acid (one case), and vinorelbine (one case).

"The Oktoberfest resulted neither in a significant increase in the absolute number of alcohol-induced acute pancreatitis [cases], nor in the percentage of alcohol-induced pancreatitis [cases], compared to other etiologies," Dr. Phillip and his associates said.

In an analysis of risk factors for admission with alcohol-induced acute pancreatitis, neither attendance at Oktoberfest nor hospitalization during the Oktoberfest period were significant predictors. In contrast, chronic alcohol intake, chronic nicotine intake, and number of previous episodes of pancreatitis all were predictive.

Forty of the 188 cases of acute pancreatitis in this study required intensive care, and five patients (2.7%) died during hospitalization. Overall, the mean duration of hospital stay was 12.3 days.

This study was not supported by any industry or other grants, and no financial conflicts of interest were reported for any of the authors.

The incidence of acute pancreatitis did not rise during or immediately after "the world’s largest beer fair," Oktoberfest in Munich, even though an estimated 6.6 million liters of beer were consumed there in only 16 days, Dr. Veit Phillip and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This unexpected result indicates that "acute attacks of alcoholic pancreatitis seem to be associated with long-term, heavy alcohol exposure rather than short-term, excessive alcohol drinking," the investigators wrote (Clin. Gastroenterol. Hepatol. 2011 [doi: 10.1016/j.cgh.2011.07.022]).

©Dan Race/Fotolia.com

Noting that "little is known about the impact of short-term aggravation of alcohol consumption on the incidence of pancreatitis," Dr. Phillip and his associates assessed the affects of Oktoberfest by studying consecutive patients admitted to 27 of the 31 hospitals in the Munich area with acute pancreatitis during the celebration and during two control periods in 2008.

The more than 6 million L of beer imbibed between Sept. 20 and Oct. 5 at Oktoberfest that year contained 340 million g pure alcohol. Hospital admissions for acute pancreatitis from Sept. 20 through Oct. 7 were compared with those from the 18-day interval immediately preceding the study period and the 18-day interval immediately following it. Each period included 6 weekend days.

A total of 91% of the admitted patients were permanent residents of the Munich area rather than visitors. A total of 188 patients were admitted for acute pancreatitis during all 54 days of observation, for an overall incidence of 42.8/100,000 person-years.

This rate is 117% higher than the rate reported for another region of Germany in an earlier study. "Because our data are the first to be analyzed from this population, we do not know if there has been an increase [in acute pancreatitis] over the last few years," or if the discrepancy is due to different drinking habits between the two regions, said Dr. Phillip of Technische Universität München and his colleagues.

The incidence of acute pancreatitis admissions was not significantly different between Oktoberfest (42.3/100,000 person-years) and the two control periods (43.0/100,000 person-years).

In fact, slightly more cases developed during the first control period (37.2% of all cases) than during Oktoberfest (33.0%) or the second control period (29.8%). This may be because the first control period coincided with the end of the summer holidays in that region, the researchers said.

Alcohol was listed as the most common etiology for acute pancreatitis (36.7% of cases), including 15 cases of acute alcohol-induced attacks in patients who had longstanding chronic pancreatitis. A biliary etiology also was common (34.6% of cases).

Less common were post-ERCP [endoscopic retrograde cholangiopancreatography] pancreatitis (3.2%) and postsurgical pancreatitis (2.7%). Drug toxicity was cited as the etiology in 4.3% of cases, and was attributed to NSAIDs (four cases), azathioprine (two cases), 5-aminosalicylic acid (one case), and vinorelbine (one case).

"The Oktoberfest resulted neither in a significant increase in the absolute number of alcohol-induced acute pancreatitis [cases], nor in the percentage of alcohol-induced pancreatitis [cases], compared to other etiologies," Dr. Phillip and his associates said.

In an analysis of risk factors for admission with alcohol-induced acute pancreatitis, neither attendance at Oktoberfest nor hospitalization during the Oktoberfest period were significant predictors. In contrast, chronic alcohol intake, chronic nicotine intake, and number of previous episodes of pancreatitis all were predictive.

Forty of the 188 cases of acute pancreatitis in this study required intensive care, and five patients (2.7%) died during hospitalization. Overall, the mean duration of hospital stay was 12.3 days.

This study was not supported by any industry or other grants, and no financial conflicts of interest were reported for any of the authors.

The incidence of acute pancreatitis did not rise during or immediately after "the world’s largest beer fair," Oktoberfest in Munich, even though an estimated 6.6 million liters of beer were consumed there in only 16 days, Dr. Veit Phillip and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This unexpected result indicates that "acute attacks of alcoholic pancreatitis seem to be associated with long-term, heavy alcohol exposure rather than short-term, excessive alcohol drinking," the investigators wrote (Clin. Gastroenterol. Hepatol. 2011 [doi: 10.1016/j.cgh.2011.07.022]).

©Dan Race/Fotolia.com

Noting that "little is known about the impact of short-term aggravation of alcohol consumption on the incidence of pancreatitis," Dr. Phillip and his associates assessed the affects of Oktoberfest by studying consecutive patients admitted to 27 of the 31 hospitals in the Munich area with acute pancreatitis during the celebration and during two control periods in 2008.

The more than 6 million L of beer imbibed between Sept. 20 and Oct. 5 at Oktoberfest that year contained 340 million g pure alcohol. Hospital admissions for acute pancreatitis from Sept. 20 through Oct. 7 were compared with those from the 18-day interval immediately preceding the study period and the 18-day interval immediately following it. Each period included 6 weekend days.

A total of 91% of the admitted patients were permanent residents of the Munich area rather than visitors. A total of 188 patients were admitted for acute pancreatitis during all 54 days of observation, for an overall incidence of 42.8/100,000 person-years.

This rate is 117% higher than the rate reported for another region of Germany in an earlier study. "Because our data are the first to be analyzed from this population, we do not know if there has been an increase [in acute pancreatitis] over the last few years," or if the discrepancy is due to different drinking habits between the two regions, said Dr. Phillip of Technische Universität München and his colleagues.

The incidence of acute pancreatitis admissions was not significantly different between Oktoberfest (42.3/100,000 person-years) and the two control periods (43.0/100,000 person-years).

In fact, slightly more cases developed during the first control period (37.2% of all cases) than during Oktoberfest (33.0%) or the second control period (29.8%). This may be because the first control period coincided with the end of the summer holidays in that region, the researchers said.

Alcohol was listed as the most common etiology for acute pancreatitis (36.7% of cases), including 15 cases of acute alcohol-induced attacks in patients who had longstanding chronic pancreatitis. A biliary etiology also was common (34.6% of cases).

Less common were post-ERCP [endoscopic retrograde cholangiopancreatography] pancreatitis (3.2%) and postsurgical pancreatitis (2.7%). Drug toxicity was cited as the etiology in 4.3% of cases, and was attributed to NSAIDs (four cases), azathioprine (two cases), 5-aminosalicylic acid (one case), and vinorelbine (one case).

"The Oktoberfest resulted neither in a significant increase in the absolute number of alcohol-induced acute pancreatitis [cases], nor in the percentage of alcohol-induced pancreatitis [cases], compared to other etiologies," Dr. Phillip and his associates said.

In an analysis of risk factors for admission with alcohol-induced acute pancreatitis, neither attendance at Oktoberfest nor hospitalization during the Oktoberfest period were significant predictors. In contrast, chronic alcohol intake, chronic nicotine intake, and number of previous episodes of pancreatitis all were predictive.

Forty of the 188 cases of acute pancreatitis in this study required intensive care, and five patients (2.7%) died during hospitalization. Overall, the mean duration of hospital stay was 12.3 days.

This study was not supported by any industry or other grants, and no financial conflicts of interest were reported for any of the authors.

A small proportion of U.S. patients thought to have drug-induced liver injury actually has hepatitis E infection, and testing for this infection should be considered under certain circumstances, reported Dr. Timothy J. Davern and his colleagues in the November issue of Gastroenterology.

In a study of serum samples and medical records from 318 cases in the Drug-Induced Liver Injury Network (DILIN), 50 cases (16%) tested positive for anti-HEV IgG (indicating previous hepatitis E infection), including 9 (3% of total cases) that were also positive for anti-HEV IgM (indicating more recent hepatitis E infection), wrote Dr. Davern of the department of transplantation at California Pacific Medical Center, San Francisco, and his associates.

The diagnosis of drug-induced liver damage is often challenging because there are no specific biomarkers for it, and the clinical features are nonspecific. "In essence, the diagnosis requires exclusion of a wide array of other causes of liver injury, including viral and autoimmune hepatitis, bile duct obstruction, sepsis, hepatic ischemia, and metabolic disorders," the investigators wrote (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.07.051]).

Testing for hepatitis A, B, and C is routinely done in cases of suspected drug-induced liver injury, but hepatitis E is rarely considered in the differential diagnosis in the United States, mainly because this type of hepatitis is believed to be rare in developed countries unless the patient has recently traveled to an endemic area such as Asia, northeast Africa, the Middle East, or Mexico. However, indigenous cases of acute hepatitis E recently have been reported in the United States, Europe, Japan, and New Zealand, and recent population-based surveys have shown that 20% or more of American adults have serologic evidence of past HEV infection.

Moreover, two potential reservoirs in Western societies have been proposed: farm and wild animals, particularly swine and game, and chronically immunosuppressed patients, who can carry high viral loads.

Given these new developments, clinicians now should consider testing for HEV in the following scenarios: when the clinical presentation of the liver damage is unusual; when the pattern of injury resembles acute viral hepatitis even though hepatitis A, B, and C have been ruled out; and especially when the drug that is suspected to have caused the liver injury is critically important to the patient (such as antiretrovirals or antituberculosis agents), Dr. Davern and his colleagues said.

They assessed serum samples from the first 318 patients enrolled in the DILIN in 2004-2009, which drew subjects from San Francisco, Indiana, Connecticut, and North Carolina.

Fifty cases (16%) were found to be reactive for IgG anti-HEV, indicating remote or resolved infection, and nine cases (3%) were also reactive for IgM anti-HEV, indicating more active or recent infection.

These nine cases were similar to those with no evidence of HEV infection in initial and peak serum bilirubin levels, alanine aminotransferase levels, alkaline phosphatase levels, the distribution pattern of serum enzyme elevations, and liver damage severity scores. None of the nine cases reported exposures to farm animals or raw pork, and none had a history of travel to an endemic area.

Eight of the nine cases had major comorbidities including HIV infection, chronic obstructive pulmonary disease, asthma, alcoholism, obesity, tuberculosis, diabetes, atherosclerosis, and lymphoma.

After a careful reanalysis of these cases, most were thought to result from hepatitis E infection, although some were still considered more likely to be related to drug hepatotoxicity. "Coincidental, subclinical hepatitis E may have preceded the acute liver injury caused by the implicated medication" in some cases, the researchers said.

The study findings suggest that HEV infection should be considered when drug-induced liver injury is suspected. In addition, immunosuppressed patients with chronic unexplained liver disease should be tested for HEV infection.

Currently, there are no FDA-approved assays for anti-HEV with proven specificity and sensitivity. "Research testing results can be obtained from the Centers for Disease Control and Prevention or by special arrangements with research laboratories," Dr. Davern and his associates said.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Cancer Institute. Dr. Davern’s associates reported ties to Teva Pharmaceuticals, KaroBio, Johnson & Johnson, Salix, Gilead Sciences, Eli Lilly, Genentech, Bristol-Myers Squibb, GlaxoSmithKline, and Medtronic.

A small proportion of U.S. patients thought to have drug-induced liver injury actually has hepatitis E infection, and testing for this infection should be considered under certain circumstances, reported Dr. Timothy J. Davern and his colleagues in the November issue of Gastroenterology.

In a study of serum samples and medical records from 318 cases in the Drug-Induced Liver Injury Network (DILIN), 50 cases (16%) tested positive for anti-HEV IgG (indicating previous hepatitis E infection), including 9 (3% of total cases) that were also positive for anti-HEV IgM (indicating more recent hepatitis E infection), wrote Dr. Davern of the department of transplantation at California Pacific Medical Center, San Francisco, and his associates.

The diagnosis of drug-induced liver damage is often challenging because there are no specific biomarkers for it, and the clinical features are nonspecific. "In essence, the diagnosis requires exclusion of a wide array of other causes of liver injury, including viral and autoimmune hepatitis, bile duct obstruction, sepsis, hepatic ischemia, and metabolic disorders," the investigators wrote (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.07.051]).

Testing for hepatitis A, B, and C is routinely done in cases of suspected drug-induced liver injury, but hepatitis E is rarely considered in the differential diagnosis in the United States, mainly because this type of hepatitis is believed to be rare in developed countries unless the patient has recently traveled to an endemic area such as Asia, northeast Africa, the Middle East, or Mexico. However, indigenous cases of acute hepatitis E recently have been reported in the United States, Europe, Japan, and New Zealand, and recent population-based surveys have shown that 20% or more of American adults have serologic evidence of past HEV infection.

Moreover, two potential reservoirs in Western societies have been proposed: farm and wild animals, particularly swine and game, and chronically immunosuppressed patients, who can carry high viral loads.

Given these new developments, clinicians now should consider testing for HEV in the following scenarios: when the clinical presentation of the liver damage is unusual; when the pattern of injury resembles acute viral hepatitis even though hepatitis A, B, and C have been ruled out; and especially when the drug that is suspected to have caused the liver injury is critically important to the patient (such as antiretrovirals or antituberculosis agents), Dr. Davern and his colleagues said.

They assessed serum samples from the first 318 patients enrolled in the DILIN in 2004-2009, which drew subjects from San Francisco, Indiana, Connecticut, and North Carolina.

Fifty cases (16%) were found to be reactive for IgG anti-HEV, indicating remote or resolved infection, and nine cases (3%) were also reactive for IgM anti-HEV, indicating more active or recent infection.

These nine cases were similar to those with no evidence of HEV infection in initial and peak serum bilirubin levels, alanine aminotransferase levels, alkaline phosphatase levels, the distribution pattern of serum enzyme elevations, and liver damage severity scores. None of the nine cases reported exposures to farm animals or raw pork, and none had a history of travel to an endemic area.

Eight of the nine cases had major comorbidities including HIV infection, chronic obstructive pulmonary disease, asthma, alcoholism, obesity, tuberculosis, diabetes, atherosclerosis, and lymphoma.

After a careful reanalysis of these cases, most were thought to result from hepatitis E infection, although some were still considered more likely to be related to drug hepatotoxicity. "Coincidental, subclinical hepatitis E may have preceded the acute liver injury caused by the implicated medication" in some cases, the researchers said.

The study findings suggest that HEV infection should be considered when drug-induced liver injury is suspected. In addition, immunosuppressed patients with chronic unexplained liver disease should be tested for HEV infection.

Currently, there are no FDA-approved assays for anti-HEV with proven specificity and sensitivity. "Research testing results can be obtained from the Centers for Disease Control and Prevention or by special arrangements with research laboratories," Dr. Davern and his associates said.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Cancer Institute. Dr. Davern’s associates reported ties to Teva Pharmaceuticals, KaroBio, Johnson & Johnson, Salix, Gilead Sciences, Eli Lilly, Genentech, Bristol-Myers Squibb, GlaxoSmithKline, and Medtronic.

A small proportion of U.S. patients thought to have drug-induced liver injury actually has hepatitis E infection, and testing for this infection should be considered under certain circumstances, reported Dr. Timothy J. Davern and his colleagues in the November issue of Gastroenterology.

In a study of serum samples and medical records from 318 cases in the Drug-Induced Liver Injury Network (DILIN), 50 cases (16%) tested positive for anti-HEV IgG (indicating previous hepatitis E infection), including 9 (3% of total cases) that were also positive for anti-HEV IgM (indicating more recent hepatitis E infection), wrote Dr. Davern of the department of transplantation at California Pacific Medical Center, San Francisco, and his associates.

The diagnosis of drug-induced liver damage is often challenging because there are no specific biomarkers for it, and the clinical features are nonspecific. "In essence, the diagnosis requires exclusion of a wide array of other causes of liver injury, including viral and autoimmune hepatitis, bile duct obstruction, sepsis, hepatic ischemia, and metabolic disorders," the investigators wrote (Gastroenterology 2011 [doi:10.1053/j.gastro.2011.07.051]).

Testing for hepatitis A, B, and C is routinely done in cases of suspected drug-induced liver injury, but hepatitis E is rarely considered in the differential diagnosis in the United States, mainly because this type of hepatitis is believed to be rare in developed countries unless the patient has recently traveled to an endemic area such as Asia, northeast Africa, the Middle East, or Mexico. However, indigenous cases of acute hepatitis E recently have been reported in the United States, Europe, Japan, and New Zealand, and recent population-based surveys have shown that 20% or more of American adults have serologic evidence of past HEV infection.

Moreover, two potential reservoirs in Western societies have been proposed: farm and wild animals, particularly swine and game, and chronically immunosuppressed patients, who can carry high viral loads.

Given these new developments, clinicians now should consider testing for HEV in the following scenarios: when the clinical presentation of the liver damage is unusual; when the pattern of injury resembles acute viral hepatitis even though hepatitis A, B, and C have been ruled out; and especially when the drug that is suspected to have caused the liver injury is critically important to the patient (such as antiretrovirals or antituberculosis agents), Dr. Davern and his colleagues said.

They assessed serum samples from the first 318 patients enrolled in the DILIN in 2004-2009, which drew subjects from San Francisco, Indiana, Connecticut, and North Carolina.

Fifty cases (16%) were found to be reactive for IgG anti-HEV, indicating remote or resolved infection, and nine cases (3%) were also reactive for IgM anti-HEV, indicating more active or recent infection.

These nine cases were similar to those with no evidence of HEV infection in initial and peak serum bilirubin levels, alanine aminotransferase levels, alkaline phosphatase levels, the distribution pattern of serum enzyme elevations, and liver damage severity scores. None of the nine cases reported exposures to farm animals or raw pork, and none had a history of travel to an endemic area.

Eight of the nine cases had major comorbidities including HIV infection, chronic obstructive pulmonary disease, asthma, alcoholism, obesity, tuberculosis, diabetes, atherosclerosis, and lymphoma.

After a careful reanalysis of these cases, most were thought to result from hepatitis E infection, although some were still considered more likely to be related to drug hepatotoxicity. "Coincidental, subclinical hepatitis E may have preceded the acute liver injury caused by the implicated medication" in some cases, the researchers said.

The study findings suggest that HEV infection should be considered when drug-induced liver injury is suspected. In addition, immunosuppressed patients with chronic unexplained liver disease should be tested for HEV infection.

Currently, there are no FDA-approved assays for anti-HEV with proven specificity and sensitivity. "Research testing results can be obtained from the Centers for Disease Control and Prevention or by special arrangements with research laboratories," Dr. Davern and his associates said.

This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Cancer Institute. Dr. Davern’s associates reported ties to Teva Pharmaceuticals, KaroBio, Johnson & Johnson, Salix, Gilead Sciences, Eli Lilly, Genentech, Bristol-Myers Squibb, GlaxoSmithKline, and Medtronic.