WASHINGTON – Statins lowered all-cause mortality by 32% in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in a retrospective cohort study.

The magnitude of benefit from statins in these two disease states is greater than that found in the general population (estimated 9%-14% reduction in all-cause mortality) and than that reported in patients with rheumatoid arthritis (RA, 21% reduction), said Amar Oza, MD, a second-year rheumatology fellow at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“This is a unique study. The benefit of statins has not been looked at in AS and PsA, specifically,” Dr. Oza explained. “More data are needed” to establish this benefit with certainty, he added.

The data were presented at the annual meeting of the American College of Rheumatology, and Dr. Oza discussed the findings in a video interview.

The study compared 2,904 patients with AS or PsA who initiated statins between 2000 and 2014 with 2,904 propensity-matched AS or PsA patients who did not initiate statins during that period. Patients were drawn from a United Kingdom general population database.

The investigators used a propensity score that accounted for 50 confounding variables to match the two cohorts. These variables included, but were not limited to, disease duration, socioeconomic status, body mass index, lifestyle factors, and medication use.

“This study is the first step in elucidating the benefit of statins in AS and PsA. It is a good step forward. If additional data substantiate that AS and PsA patients have a low threshold for statins, I can envision statins for both primary and secondary prevention in this patient population,” Dr. Oza stated.

The authors had no relevant financial disclosures.

WASHINGTON – Statins lowered all-cause mortality by 32% in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in a retrospective cohort study.

The magnitude of benefit from statins in these two disease states is greater than that found in the general population (estimated 9%-14% reduction in all-cause mortality) and than that reported in patients with rheumatoid arthritis (RA, 21% reduction), said Amar Oza, MD, a second-year rheumatology fellow at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“This is a unique study. The benefit of statins has not been looked at in AS and PsA, specifically,” Dr. Oza explained. “More data are needed” to establish this benefit with certainty, he added.

The data were presented at the annual meeting of the American College of Rheumatology, and Dr. Oza discussed the findings in a video interview.

The study compared 2,904 patients with AS or PsA who initiated statins between 2000 and 2014 with 2,904 propensity-matched AS or PsA patients who did not initiate statins during that period. Patients were drawn from a United Kingdom general population database.

The investigators used a propensity score that accounted for 50 confounding variables to match the two cohorts. These variables included, but were not limited to, disease duration, socioeconomic status, body mass index, lifestyle factors, and medication use.

“This study is the first step in elucidating the benefit of statins in AS and PsA. It is a good step forward. If additional data substantiate that AS and PsA patients have a low threshold for statins, I can envision statins for both primary and secondary prevention in this patient population,” Dr. Oza stated.

The authors had no relevant financial disclosures.

WASHINGTON – Statins lowered all-cause mortality by 32% in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in a retrospective cohort study.

The magnitude of benefit from statins in these two disease states is greater than that found in the general population (estimated 9%-14% reduction in all-cause mortality) and than that reported in patients with rheumatoid arthritis (RA, 21% reduction), said Amar Oza, MD, a second-year rheumatology fellow at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“This is a unique study. The benefit of statins has not been looked at in AS and PsA, specifically,” Dr. Oza explained. “More data are needed” to establish this benefit with certainty, he added.

The data were presented at the annual meeting of the American College of Rheumatology, and Dr. Oza discussed the findings in a video interview.

The study compared 2,904 patients with AS or PsA who initiated statins between 2000 and 2014 with 2,904 propensity-matched AS or PsA patients who did not initiate statins during that period. Patients were drawn from a United Kingdom general population database.

The investigators used a propensity score that accounted for 50 confounding variables to match the two cohorts. These variables included, but were not limited to, disease duration, socioeconomic status, body mass index, lifestyle factors, and medication use.

“This study is the first step in elucidating the benefit of statins in AS and PsA. It is a good step forward. If additional data substantiate that AS and PsA patients have a low threshold for statins, I can envision statins for both primary and secondary prevention in this patient population,” Dr. Oza stated.

The authors had no relevant financial disclosures.

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

People with Alzheimer’s disease have different daily patterns of activity, compared with healthy controls, according to research published online ahead of print October 4 in the Journal of Alzheimer’s Disease. Understanding this different daily pattern in physical activity could be key to designing interventions and improving sleep for people with early Alzheimer’s disease, perhaps by targeting more physical activity in morning, said the researchers.

Too little is known about patterns of activity for people experiencing the early stages of Alzheimer’s disease, according to Amber Watts, PhD, Assistant Professor of Clinical Psychology at the University of Kansas in Lawrence. For instance, researchers have lacked useful data about how the progression of the disease itself plays a role in diminishing day-to-day physical activity.

Vijay R. Varma, PhD, a postdoctoral fellow at the National Institute on Aging, and Dr. Watts analyzed the daily physical activity of 92 volunteers with and without mild Alzheimer’s disease at the University of Kansas’s Alzheimer’s Disease Center in Kansas City. Participants wore Actigraph GT3X+ accelerometers for a week.Mild Alzheimer’s disease was associated with less moderate-intensity physical activity, lower peak activity, and lower physical activity complexity, particularly during the morning. Mild Alzheimer’s disease was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for noncognitive covariates.

The kinds of physical activity helpful to people with Alzheimer’s disease might be simple activities such as finding time to walk around the neighborhood, said Dr. Watts. “Walking is actually the best thing,” she said. “It is low risk, it is safe, anyone can do it, it doesn’t require specific equipment, it can be done anywhere. There are other light-intensity activities like stretching, tai chi, household chores, gardening, walking around the mall—those are also beneficial. People with Alzheimer’s disease do not have to go to the gym, they just need to do something that keeps them moving and keeps them from sitting continuously.”

Suggested Reading

Varma VR, Watts A. Daily physical activity patterns during the early stage of Alzheimer’s disease. J Alzheimers Dis. 2016 Oct 4 [Epub ahead of print].

WASHINGTON – Resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an acceptable alternative to thoracotomy in traumatic arrest patients who are hemorrhaging below the diaphragm, according to the results of a small pilot study which were presented by William Teeter, MD, at the annual clinical congress of the American College of Surgeons.

Furthermore, virtual simulation training sufficiently prepares surgeons to safely use the REBOA technique in the acute care setting, a separate study found. Importantly, this training has the potential to allow REBOA to become a widespread tool for surgeons regardless of their endovascular surgical experience.

XiXinXing/ThinkStock

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

WASHINGTON – Resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an acceptable alternative to thoracotomy in traumatic arrest patients who are hemorrhaging below the diaphragm, according to the results of a small pilot study which were presented by William Teeter, MD, at the annual clinical congress of the American College of Surgeons.

Furthermore, virtual simulation training sufficiently prepares surgeons to safely use the REBOA technique in the acute care setting, a separate study found. Importantly, this training has the potential to allow REBOA to become a widespread tool for surgeons regardless of their endovascular surgical experience.

XiXinXing/ThinkStock

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

WASHINGTON – Resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an acceptable alternative to thoracotomy in traumatic arrest patients who are hemorrhaging below the diaphragm, according to the results of a small pilot study which were presented by William Teeter, MD, at the annual clinical congress of the American College of Surgeons.

Furthermore, virtual simulation training sufficiently prepares surgeons to safely use the REBOA technique in the acute care setting, a separate study found. Importantly, this training has the potential to allow REBOA to become a widespread tool for surgeons regardless of their endovascular surgical experience.

XiXinXing/ThinkStock

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

WASHINGTON, DC—Fifty-seven new drugs for Alzheimer’s disease currently are in phase II studies, according to an analysis conducted by Researchers Against Alzheimer’s (RA2). Nearly twice as many mechanisms of action are being tested in phase II than in phase III clinical trials, the group said. This diverse pipeline could provide physicians, persons with Alzheimer’s disease, and their loved ones with new ways to combat the disease in the future.

Advancements in Alzheimer’s Disease Drug Development

As the development of these compounds progresses, and the science of Alzheimer’s disease drug development advances, policy makers, clinical researchers, drug developers, and other Alzheimer’s disease drug partners need to create new clinical trial infrastructure and designs that allow for rapid recruitment and testing, consistent high-quality data, and prompt data disclosure, said RA2.

“These potentially game-changing drugs on the horizon may make Alzheimer’s [disease] a manageable disease,” said George Vradenburg, Cofounder and Chair of USAgainstAlzheimer’s, a group that advocates for a cure for Alzheimer’s disease. “To assure our best shot at success, we must ensure that the necessary investments are being made to build a 21st-century infrastructure to test their effectiveness and an innovation-friendly path to market [for] those in need,” he said.

The first RA2 pipeline analysis released in March found 17 Alzheimer’s disease drugs in phase III clinical trials planned to launch in the next five years. However, since the initial phase III pipeline report was issued, several Alzheimer’s disease drug candidates have moved from phase II to phase III clinical trials. According to the most recent analysis, 23 Alzheimer’s disease drugs are in phase III clinical trials. In all, 19 drugs could reach the market in the next five years, according to RA2.

Researchers and pharmaceutical companies are increasingly focusing on disease-modifying prevention drugs, such as those that can be administered to people at risk for Alzheimer’s disease before symptoms appear. These drugs could prevent or delay the development of dementia symptoms.

A similar approach is used to prevent people who are HIV-positive from developing AIDS symptoms. These drugs represent a different approach from symptomatic drugs, which are intended to treat Alzheimer’s disease symptoms such as agitation, cognitive loss, hallucinations, or depression.

Several changes are required to maintain a diverse pipeline of preventive and symptomatic drugs, according to the analysis, which was reviewed by academic research experts and select RA2 members. These changes include a standing, high-performance clinical trial infrastructure that allows for rapid testing and fast failure or success.

In addition, the field needs robust biomarkers that help to indicate disease severity or progression and help to assess the effectiveness of drugs in populations without any symptoms, potentially preventing the development of symptoms altogether, according to the analysis. A greater understanding of biomarker research will assist researchers and clinicians to prescribe medicines to the appropriate populations.

New end points for trials are another necessary change, said the group. Many of the current scales used in Alzheimer’s disease trials will not be effective in people in early stages of the disease, since symptoms like cognitive decline may occur late in the disease.

Clinicians and researchers also should develop mechanisms for actively sharing information about which treatments work best with certain patient populations, according to the analysis.

Finally, the field requires innovative clinical trial designs to increase flexibility for drug developers. Such designs include adaptive trials that are modified based on patient outcomes, as well as trials of combinations of novel treatments. The latter trials could include drugs with demonstrated target engagement, but without efficacy as monotherapy.

Phase II/III and Phase III Drug Trials

Trials of several phase II/III drugs and one phase III drug will be completed in 2017. The phase II/III treatments include AC-1204, an oral drug intended for patients with mild to moderate Alzheimer’s disease that improves mitochondrial metabolism through chronic ketosis. A combination of albumin and immunoglobulin is being studied for patients with mild to moderate Alzheimer’s disease. It is an IV immunosuppressant with possible antiamyloid antibodies and albumin-binding capacity. Finally, a phase III trial of suvorexant, an oral orexin receptor antagonist under investigation for patients with Alzheimer’s disease and insomnia, will conclude in 2017.

“I am encouraged to see such a range of approaches to treating Alzheimer’s [disease] in phase II development,” said David Morgan, PhD, CEO of the Byrd Alzheimer Institute at the University of South Florida in Tampa. “There is much work that still needs to be done, but the drugs in phase II clinical trials offer a great deal of hope for the future,” he added.

—Erica Tricarico

Suggested Reading

Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.

Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

aotto@frontlinemedcom.com

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

aotto@frontlinemedcom.com

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

aotto@frontlinemedcom.com