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Pain: What We Have Achieved in the Past 25 Years
Sait Ashina, MD; Kimberly Sackheim, DO; Christopher Gharibo, MD
Dr. Ashina is Clinical Associate Professor, Department of Neurology, and Director of the Headache Center at NYU Langone Medical Center, New York, NY
Dr. Sackheim is Clinical Assistant Professor, Department of Rehabilitation Medicine, NYU Langone Medical Center, New York, NY
Dr. Gharibo is Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Langone Medical Center, New York, NY
Pain is one of the most prevalent medical complaints and one of the most common reasons people seek medical attention in the United States. Chronic pain has an enormous impact on the individual and is associated with high societal costs. Because of these facts, it is considered a major health problem in the United States. The pathophysiologic mechanisms of acute and chronic pain are not fully understood, and chronic pain remains poorly recognized and undertreated. However, in the past 25 years, there have been major advances in our understanding of pain. New agents, medications, and techniques for the treatment of acute and chronic pain have emerged. 
Recognizing the undertreatment of pain, the Agency for Health Care Policy and Research at the US Department of Health and Human Services issued the Acute Pain Management: Operative or Medical Procedures and Trauma guidelines in 1992.1 Subsequent years have witnessed increasing use of patient-controlled analgesia, postoperative analgesia, continuous peripheral nerve blocks, and development of new therapeutic and pharmacologic modalities. The recognition of pain medicine as a subspecialty in medicine across multiple specialties is one of the field’s major achievements. The first pain medicine fellowships were accredited in 1993. The number of programs increased to almost 100 by 1999,2 and more programs are being accredited now. 
With regard to the pathophysiologic mechanisms of chronic pain, we gained a better understanding of central sensitization through research published in the late 1980s that describes activity-dependent synaptic plasticity in the nociceptive pathways.3 Central sensitization is triggered and maintained by nociceptor input. Central sensitization changes the sensitivity of the pain system so that normally innocuous stimulation can activate it. The responses to pain become exaggerated and can be widespread. Substantial progress has been made in understanding the cellular and molecular mechanisms involved in central sensitization, which was initially described as a physiologic phenomenon. Interestingly, glial cells, such as microglia and astrocytes, were reported to contribute to central sensitization in the setting of injury. Advanced neuroimaging techniques reveal that pain is processed in several areas of the brain. PET and functional MRI (fMRI) have provided a deeper understanding of the perception of pain by an extensive mapping of the neural pathways associated with pain: the so-called “pain matrix.”
In the past 25 years, many new drugs have been introduced for the treatment of acute and chronic pain.4 Antiepileptic and antidepressant medications have been increasingly used for the treatment of several chronic neuropathic pain conditions.
Gabapentin, a structural analog of gamma-aminobutyric acid, was introduced in 1994 as an antiepileptic drug. Placebo-controlled clinical trials have shown gabapentin to be effective in treating pain related to diabetic neuropathy and postherpetic neuralgia.
A successor of gabapentin, pregabalin, is an antagonist of voltage-gated Ca2+ channels. An antiepileptic agent, pregabalin has been shown to be effective in different types of neuropathic pain, including peripheral diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, and cancer chemotherapy-induced neuropathic pain.
Duloxetine, a serotonin and noradrenaline reuptake inhibitor and antidepressant, was shown to be effective in the management of neuropathic pain associated with diabetic peripheral neuropathy, as well as fibromyalgia and chronic musculoskeletal pain, including pain in osteoarthritis and chronic low back pain.
Cyclo-oxygenase-2 (COX-2) inhibitors, developed to avoid the gastrointestinal complications of NSAIDs, were introduced in 1999. Celecoxib was the first COX-2 inhibitor available on the market. COX-2 inhibitors provide anti-inflammatory and analgesic activities similar to those of conventional NSAIDs, but with fewer gastrointestinal complications, which results largely from COX-1 inhibition.
Meloxicam, often classed as a conventional NSAID but with preferential COX-2 inhibition at lower doses, was introduced in the late 1990s and has been extensively used for the treatment of acute and chronic pain.
There is growing interest in the role of cannabinoids in the management of chronic pain. Cannabinoid agents are legal for the treatment of chronic pain in several states, but not legal federally, which discourages most physicians from prescribing them.
In December 1995, the FDA approved oxycontin, an extended-release formulation of oxycodone, a semisynthetic opioid for the treatment of chronic pain. The goal was to deter abuse of the original immediate-release oxycodone by controlling the amount of drug released to avoid the initial “high” associated with the short-acting formulation. Unfortunately, this medication did not deter abuse, and pharmaceutical companies are constantly striving to create new formulations that are more resistant to tampering.
Over the past few years, some formulations of morphine that do deter abuse have been released. Unfortunately, any opioid can still be abused, just not as easily. Opioids have been extensively prescribed for chronic pain conditions, and well-selected patients have benefited from the treatment. However, prescriptions of opioids have increased over the past two decades. As a result, increases in prescription opioid abuse and opioid-related deaths have occurred. State and national efforts have educated clinicians on how to manage pain with opioids and monitor for and treat addiction. Increasing availability of abuse-deterrent opioid formulations and the opioid antagonist naloxone, which is available in pharmacies nationwide, has been of some help.
The role of interventional techniques and use of neuromodulation in pain management has been on the increase in the past two decades. Peripheral nerve stimulation has been used for the treatment of neuropathic pain for 30 to 40 years.5 The introduction of less invasive implantation methods, MRI-compatible stimulators, paresthesia-free stimulation, and dorsal root ganglion stimulation, which are all supported by positive clinical trials, has resulted in a recent increase in the use of neuromodulation for medically refractory patients and those with chronic pain.5 Similarly, spinal cord stimulation has become an alternative for the treatment of chronic pain that is unresponsive to conservative therapies.6 The efficacy of this treatment has improved, and higher-frequency settings are available. Additionally, the use of platelet-rich plasma injections, prolotherapy, and bone marrow injections in pain management have been showing promising results and gaining increasing interest in orthopedics and sports medicine. Unfortunately, there is not enough evidence to support these treatments’ efficacy, and there is no coverage from insurance, which makes them expensive for patients and less attainable.
The American Pain Society has proposed several goals7 with the aim of reducing the burden of chronic pain by improving the understanding of pain pathophysiology and pain treatment mechanisms, developing novel pain therapies, optimizing and testing existing treatment modalities, and promoting education on pain in the future. Much more remains to be learned about the role of peripheral and central sensitization in nociception. Recent advances in imaging techniques may be of great help. With new imaging techniques, including fMRI, it may be possible to measure pain-related brain activity objectively, identify pain biomarkers, and distinguish physical from emotional features of pain. Moreover, advanced imaging may help in the search for new therapeutic agents for acute and chronic pain. More research on potential genetic and environmental risk factors responsible for the development of central sensitization is warranted.
Calcitonin gene-related peptide (CGRP) is a neuropeptide that is widely distributed in the nociceptive system in humans. CGRP has been shown to play a role in the pathophysiology of migraine, and blocking it is the rationale behind the recent development of CGRP receptor antagonists and monoclonal antibodies against CGRP for the treatment of migraine. CGRP may play a role in pain transmission and have a proinflammatory role in nociception.8 Improved understanding of these mechanisms may result in the development of new anti-GGRP pharmacologic agents in non-headache pain conditions.
The pharmacogenomics of pain management is an evolving field in pain medicine. More studies are needed to identify genomic variations that can predict response to analgesic drugs. Lastly, further research and studies are needed to suggest use of the stem cell therapy in pain management, but overall, the field is constantly growing, and new therapies are emerging to help avoid the use of potentially addictive medications.
References
1. Acute pain management: operative or medical procedures and trauma, part 2. Agency for Health Care Policy and Research. Clin Pharm. 1992;11(5):391-414.
2. Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-1769.
4. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg. 2010;110(3):780-789.
5. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100-106.
6. Bicket MC, Dunn RY, Ahmed SU. High-frequency spinal cord stimulation for chronic pain: pre-clinical overview and systematic review of controlled trials. Pain Med. 2016;17(12):2326-2336.
7. Gereau RW 4th, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. J Pain. 2014;15(12):1203-1214.
8. Schou WS, Ashina S, Amin FM, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.
Sait Ashina, MD; Kimberly Sackheim, DO; Christopher Gharibo, MD
Dr. Ashina is Clinical Associate Professor, Department of Neurology, and Director of the Headache Center at NYU Langone Medical Center, New York, NY
Dr. Sackheim is Clinical Assistant Professor, Department of Rehabilitation Medicine, NYU Langone Medical Center, New York, NY
Dr. Gharibo is Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Langone Medical Center, New York, NY
Pain is one of the most prevalent medical complaints and one of the most common reasons people seek medical attention in the United States. Chronic pain has an enormous impact on the individual and is associated with high societal costs. Because of these facts, it is considered a major health problem in the United States. The pathophysiologic mechanisms of acute and chronic pain are not fully understood, and chronic pain remains poorly recognized and undertreated. However, in the past 25 years, there have been major advances in our understanding of pain. New agents, medications, and techniques for the treatment of acute and chronic pain have emerged.
Recognizing the undertreatment of pain, the Agency for Health Care Policy and Research at the US Department of Health and Human Services issued the Acute Pain Management: Operative or Medical Procedures and Trauma guidelines in 1992.1 Subsequent years have witnessed increasing use of patient-controlled analgesia, postoperative analgesia, continuous peripheral nerve blocks, and development of new therapeutic and pharmacologic modalities. The recognition of pain medicine as a subspecialty in medicine across multiple specialties is one of the field’s major achievements. The first pain medicine fellowships were accredited in 1993. The number of programs increased to almost 100 by 1999,2 and more programs are being accredited now.
With regard to the pathophysiologic mechanisms of chronic pain, we gained a better understanding of central sensitization through research published in the late 1980s that describes activity-dependent synaptic plasticity in the nociceptive pathways.3 Central sensitization is triggered and maintained by nociceptor input. Central sensitization changes the sensitivity of the pain system so that normally innocuous stimulation can activate it. The responses to pain become exaggerated and can be widespread. Substantial progress has been made in understanding the cellular and molecular mechanisms involved in central sensitization, which was initially described as a physiologic phenomenon. Interestingly, glial cells, such as microglia and astrocytes, were reported to contribute to central sensitization in the setting of injury. Advanced neuroimaging techniques reveal that pain is processed in several areas of the brain. PET and functional MRI (fMRI) have provided a deeper understanding of the perception of pain by an extensive mapping of the neural pathways associated with pain: the so-called “pain matrix.”
In the past 25 years, many new drugs have been introduced for the treatment of acute and chronic pain.4 Antiepileptic and antidepressant medications have been increasingly used for the treatment of several chronic neuropathic pain conditions.
Gabapentin, a structural analog of gamma-aminobutyric acid, was introduced in 1994 as an antiepileptic drug. Placebo-controlled clinical trials have shown gabapentin to be effective in treating pain related to diabetic neuropathy and postherpetic neuralgia.
A successor of gabapentin, pregabalin, is an antagonist of voltage-gated Ca2+ channels. An antiepileptic agent, pregabalin has been shown to be effective in different types of neuropathic pain, including peripheral diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, and cancer chemotherapy-induced neuropathic pain.
Duloxetine, a serotonin and noradrenaline reuptake inhibitor and antidepressant, was shown to be effective in the management of neuropathic pain associated with diabetic peripheral neuropathy, as well as fibromyalgia and chronic musculoskeletal pain, including pain in osteoarthritis and chronic low back pain.
Cyclo-oxygenase-2 (COX-2) inhibitors, developed to avoid the gastrointestinal complications of NSAIDs, were introduced in 1999. Celecoxib was the first COX-2 inhibitor available on the market. COX-2 inhibitors provide anti-inflammatory and analgesic activities similar to those of conventional NSAIDs, but with fewer gastrointestinal complications, which results largely from COX-1 inhibition.
Meloxicam, often classed as a conventional NSAID but with preferential COX-2 inhibition at lower doses, was introduced in the late 1990s and has been extensively used for the treatment of acute and chronic pain.
There is growing interest in the role of cannabinoids in the management of chronic pain. Cannabinoid agents are legal for the treatment of chronic pain in several states, but not legal federally, which discourages most physicians from prescribing them.
In December 1995, the FDA approved oxycontin, an extended-release formulation of oxycodone, a semisynthetic opioid for the treatment of chronic pain. The goal was to deter abuse of the original immediate-release oxycodone by controlling the amount of drug released to avoid the initial “high” associated with the short-acting formulation. Unfortunately, this medication did not deter abuse, and pharmaceutical companies are constantly striving to create new formulations that are more resistant to tampering.
Over the past few years, some formulations of morphine that do deter abuse have been released. Unfortunately, any opioid can still be abused, just not as easily. Opioids have been extensively prescribed for chronic pain conditions, and well-selected patients have benefited from the treatment. However, prescriptions of opioids have increased over the past two decades. As a result, increases in prescription opioid abuse and opioid-related deaths have occurred. State and national efforts have educated clinicians on how to manage pain with opioids and monitor for and treat addiction. Increasing availability of abuse-deterrent opioid formulations and the opioid antagonist naloxone, which is available in pharmacies nationwide, has been of some help.
The role of interventional techniques and use of neuromodulation in pain management has been on the increase in the past two decades. Peripheral nerve stimulation has been used for the treatment of neuropathic pain for 30 to 40 years.5 The introduction of less invasive implantation methods, MRI-compatible stimulators, paresthesia-free stimulation, and dorsal root ganglion stimulation, which are all supported by positive clinical trials, has resulted in a recent increase in the use of neuromodulation for medically refractory patients and those with chronic pain.5 Similarly, spinal cord stimulation has become an alternative for the treatment of chronic pain that is unresponsive to conservative therapies.6 The efficacy of this treatment has improved, and higher-frequency settings are available. Additionally, the use of platelet-rich plasma injections, prolotherapy, and bone marrow injections in pain management have been showing promising results and gaining increasing interest in orthopedics and sports medicine. Unfortunately, there is not enough evidence to support these treatments’ efficacy, and there is no coverage from insurance, which makes them expensive for patients and less attainable.
The American Pain Society has proposed several goals7 with the aim of reducing the burden of chronic pain by improving the understanding of pain pathophysiology and pain treatment mechanisms, developing novel pain therapies, optimizing and testing existing treatment modalities, and promoting education on pain in the future. Much more remains to be learned about the role of peripheral and central sensitization in nociception. Recent advances in imaging techniques may be of great help. With new imaging techniques, including fMRI, it may be possible to measure pain-related brain activity objectively, identify pain biomarkers, and distinguish physical from emotional features of pain. Moreover, advanced imaging may help in the search for new therapeutic agents for acute and chronic pain. More research on potential genetic and environmental risk factors responsible for the development of central sensitization is warranted.
Calcitonin gene-related peptide (CGRP) is a neuropeptide that is widely distributed in the nociceptive system in humans. CGRP has been shown to play a role in the pathophysiology of migraine, and blocking it is the rationale behind the recent development of CGRP receptor antagonists and monoclonal antibodies against CGRP for the treatment of migraine. CGRP may play a role in pain transmission and have a proinflammatory role in nociception.8 Improved understanding of these mechanisms may result in the development of new anti-GGRP pharmacologic agents in non-headache pain conditions.
The pharmacogenomics of pain management is an evolving field in pain medicine. More studies are needed to identify genomic variations that can predict response to analgesic drugs. Lastly, further research and studies are needed to suggest use of the stem cell therapy in pain management, but overall, the field is constantly growing, and new therapies are emerging to help avoid the use of potentially addictive medications.
References
1. Acute pain management: operative or medical procedures and trauma, part 2. Agency for Health Care Policy and Research. Clin Pharm. 1992;11(5):391-414.
2. Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-1769.
4. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg. 2010;110(3):780-789.
5. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100-106.
6. Bicket MC, Dunn RY, Ahmed SU. High-frequency spinal cord stimulation for chronic pain: pre-clinical overview and systematic review of controlled trials. Pain Med. 2016;17(12):2326-2336.
7. Gereau RW 4th, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. J Pain. 2014;15(12):1203-1214.
8. Schou WS, Ashina S, Amin FM, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.
Sait Ashina, MD; Kimberly Sackheim, DO; Christopher Gharibo, MD
Dr. Ashina is Clinical Associate Professor, Department of Neurology, and Director of the Headache Center at NYU Langone Medical Center, New York, NY
Dr. Sackheim is Clinical Assistant Professor, Department of Rehabilitation Medicine, NYU Langone Medical Center, New York, NY
Dr. Gharibo is Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Langone Medical Center, New York, NY
Pain is one of the most prevalent medical complaints and one of the most common reasons people seek medical attention in the United States. Chronic pain has an enormous impact on the individual and is associated with high societal costs. Because of these facts, it is considered a major health problem in the United States. The pathophysiologic mechanisms of acute and chronic pain are not fully understood, and chronic pain remains poorly recognized and undertreated. However, in the past 25 years, there have been major advances in our understanding of pain. New agents, medications, and techniques for the treatment of acute and chronic pain have emerged.
Recognizing the undertreatment of pain, the Agency for Health Care Policy and Research at the US Department of Health and Human Services issued the Acute Pain Management: Operative or Medical Procedures and Trauma guidelines in 1992.1 Subsequent years have witnessed increasing use of patient-controlled analgesia, postoperative analgesia, continuous peripheral nerve blocks, and development of new therapeutic and pharmacologic modalities. The recognition of pain medicine as a subspecialty in medicine across multiple specialties is one of the field’s major achievements. The first pain medicine fellowships were accredited in 1993. The number of programs increased to almost 100 by 1999,2 and more programs are being accredited now.
With regard to the pathophysiologic mechanisms of chronic pain, we gained a better understanding of central sensitization through research published in the late 1980s that describes activity-dependent synaptic plasticity in the nociceptive pathways.3 Central sensitization is triggered and maintained by nociceptor input. Central sensitization changes the sensitivity of the pain system so that normally innocuous stimulation can activate it. The responses to pain become exaggerated and can be widespread. Substantial progress has been made in understanding the cellular and molecular mechanisms involved in central sensitization, which was initially described as a physiologic phenomenon. Interestingly, glial cells, such as microglia and astrocytes, were reported to contribute to central sensitization in the setting of injury. Advanced neuroimaging techniques reveal that pain is processed in several areas of the brain. PET and functional MRI (fMRI) have provided a deeper understanding of the perception of pain by an extensive mapping of the neural pathways associated with pain: the so-called “pain matrix.”
In the past 25 years, many new drugs have been introduced for the treatment of acute and chronic pain.4 Antiepileptic and antidepressant medications have been increasingly used for the treatment of several chronic neuropathic pain conditions.
Gabapentin, a structural analog of gamma-aminobutyric acid, was introduced in 1994 as an antiepileptic drug. Placebo-controlled clinical trials have shown gabapentin to be effective in treating pain related to diabetic neuropathy and postherpetic neuralgia.
A successor of gabapentin, pregabalin, is an antagonist of voltage-gated Ca2+ channels. An antiepileptic agent, pregabalin has been shown to be effective in different types of neuropathic pain, including peripheral diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, and cancer chemotherapy-induced neuropathic pain.
Duloxetine, a serotonin and noradrenaline reuptake inhibitor and antidepressant, was shown to be effective in the management of neuropathic pain associated with diabetic peripheral neuropathy, as well as fibromyalgia and chronic musculoskeletal pain, including pain in osteoarthritis and chronic low back pain.
Cyclo-oxygenase-2 (COX-2) inhibitors, developed to avoid the gastrointestinal complications of NSAIDs, were introduced in 1999. Celecoxib was the first COX-2 inhibitor available on the market. COX-2 inhibitors provide anti-inflammatory and analgesic activities similar to those of conventional NSAIDs, but with fewer gastrointestinal complications, which results largely from COX-1 inhibition.
Meloxicam, often classed as a conventional NSAID but with preferential COX-2 inhibition at lower doses, was introduced in the late 1990s and has been extensively used for the treatment of acute and chronic pain.
There is growing interest in the role of cannabinoids in the management of chronic pain. Cannabinoid agents are legal for the treatment of chronic pain in several states, but not legal federally, which discourages most physicians from prescribing them.
In December 1995, the FDA approved oxycontin, an extended-release formulation of oxycodone, a semisynthetic opioid for the treatment of chronic pain. The goal was to deter abuse of the original immediate-release oxycodone by controlling the amount of drug released to avoid the initial “high” associated with the short-acting formulation. Unfortunately, this medication did not deter abuse, and pharmaceutical companies are constantly striving to create new formulations that are more resistant to tampering.
Over the past few years, some formulations of morphine that do deter abuse have been released. Unfortunately, any opioid can still be abused, just not as easily. Opioids have been extensively prescribed for chronic pain conditions, and well-selected patients have benefited from the treatment. However, prescriptions of opioids have increased over the past two decades. As a result, increases in prescription opioid abuse and opioid-related deaths have occurred. State and national efforts have educated clinicians on how to manage pain with opioids and monitor for and treat addiction. Increasing availability of abuse-deterrent opioid formulations and the opioid antagonist naloxone, which is available in pharmacies nationwide, has been of some help.
The role of interventional techniques and use of neuromodulation in pain management has been on the increase in the past two decades. Peripheral nerve stimulation has been used for the treatment of neuropathic pain for 30 to 40 years.5 The introduction of less invasive implantation methods, MRI-compatible stimulators, paresthesia-free stimulation, and dorsal root ganglion stimulation, which are all supported by positive clinical trials, has resulted in a recent increase in the use of neuromodulation for medically refractory patients and those with chronic pain.5 Similarly, spinal cord stimulation has become an alternative for the treatment of chronic pain that is unresponsive to conservative therapies.6 The efficacy of this treatment has improved, and higher-frequency settings are available. Additionally, the use of platelet-rich plasma injections, prolotherapy, and bone marrow injections in pain management have been showing promising results and gaining increasing interest in orthopedics and sports medicine. Unfortunately, there is not enough evidence to support these treatments’ efficacy, and there is no coverage from insurance, which makes them expensive for patients and less attainable.
The American Pain Society has proposed several goals7 with the aim of reducing the burden of chronic pain by improving the understanding of pain pathophysiology and pain treatment mechanisms, developing novel pain therapies, optimizing and testing existing treatment modalities, and promoting education on pain in the future. Much more remains to be learned about the role of peripheral and central sensitization in nociception. Recent advances in imaging techniques may be of great help. With new imaging techniques, including fMRI, it may be possible to measure pain-related brain activity objectively, identify pain biomarkers, and distinguish physical from emotional features of pain. Moreover, advanced imaging may help in the search for new therapeutic agents for acute and chronic pain. More research on potential genetic and environmental risk factors responsible for the development of central sensitization is warranted.
Calcitonin gene-related peptide (CGRP) is a neuropeptide that is widely distributed in the nociceptive system in humans. CGRP has been shown to play a role in the pathophysiology of migraine, and blocking it is the rationale behind the recent development of CGRP receptor antagonists and monoclonal antibodies against CGRP for the treatment of migraine. CGRP may play a role in pain transmission and have a proinflammatory role in nociception.8 Improved understanding of these mechanisms may result in the development of new anti-GGRP pharmacologic agents in non-headache pain conditions.
The pharmacogenomics of pain management is an evolving field in pain medicine. More studies are needed to identify genomic variations that can predict response to analgesic drugs. Lastly, further research and studies are needed to suggest use of the stem cell therapy in pain management, but overall, the field is constantly growing, and new therapies are emerging to help avoid the use of potentially addictive medications.
References
1. Acute pain management: operative or medical procedures and trauma, part 2. Agency for Health Care Policy and Research. Clin Pharm. 1992;11(5):391-414.
2. Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-1769.
4. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg. 2010;110(3):780-789.
5. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100-106.
6. Bicket MC, Dunn RY, Ahmed SU. High-frequency spinal cord stimulation for chronic pain: pre-clinical overview and systematic review of controlled trials. Pain Med. 2016;17(12):2326-2336.
7. Gereau RW 4th, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. J Pain. 2014;15(12):1203-1214.
8. Schou WS, Ashina S, Amin FM, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.
Novel dermal coring device effective for facial rejuvenation without using thermal energy
DALLAS – according to preliminary results from an ongoing study.
“This differs from laser treatment in the sense that there’s no thermal injury and it takes a deep core approach, along the lines of what you might expect from a punch biopsy,” lead study author Roy G. Geronemus, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “The device causes microscale excisions below the size that causes scar. It’s mechanical only, without the use of any thermal energy. There is quantitative and directional reduction in area of skin. This leads to wrinkle improvement, tightening, smoothing of lax skin, and skin rejuvenation.”
The average age of subjects was 64 years, and all had Fitzpatrick types II or III skin. No unanticipated adverse events or serious adverse events were observed, and histology from 3 subjects showed an excellent healing profile and no scarring. The average pain during treatment was 0.36 on the 0-10 Wong-Baker scale.
Interim 90-day data demonstrated that 87% of 30 cheek areas had 1, 2, or 3 levels of improvement in moderate to severe cheek wrinkles on the Lemperle scale, according to primary investigator assessment. Investigators and subjects scored “improved to very much improved” in 93% of patients per the Global Aesthetic Improvement Scale, and 80% of the patients reported being “satisfied to extremely satisfied” with their aesthetic results.
Dr. Geronemus noted that, while it takes 2 to 7 days for wounds to close following ablative procedures, wounds close in about 10 minutes following microexcisional treatment, which possibly leads to faster healing of tissue. “Most people expect some downtime to achieve effective, long-lasting results,” he said. “The mean downtime was 3.8 days; 75% of subjects did not miss work, and 46% did not miss any social or leisure activities.”
To date, 79 subjects have been treated and a 90-day pivotal study is under way. Based on the clinical data to date, he said, “the new technique offers the ability to remove a significant amount of damaged, lax skin without concern of scarring or pigmentary change.”
Dr. Geronemus reported having served on the advisory board or as an investigator for Cynosure, Syneron Candela, Cutera, Revance Therapeutics, Allergan, Cytrellis Biosystems, the New York Stem Cell Foundation, among others. He also holds ownership interests with Cytrellis, the company that developed the coring device.
[email protected]
DALLAS – according to preliminary results from an ongoing study.
“This differs from laser treatment in the sense that there’s no thermal injury and it takes a deep core approach, along the lines of what you might expect from a punch biopsy,” lead study author Roy G. Geronemus, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “The device causes microscale excisions below the size that causes scar. It’s mechanical only, without the use of any thermal energy. There is quantitative and directional reduction in area of skin. This leads to wrinkle improvement, tightening, smoothing of lax skin, and skin rejuvenation.”
The average age of subjects was 64 years, and all had Fitzpatrick types II or III skin. No unanticipated adverse events or serious adverse events were observed, and histology from 3 subjects showed an excellent healing profile and no scarring. The average pain during treatment was 0.36 on the 0-10 Wong-Baker scale.
Interim 90-day data demonstrated that 87% of 30 cheek areas had 1, 2, or 3 levels of improvement in moderate to severe cheek wrinkles on the Lemperle scale, according to primary investigator assessment. Investigators and subjects scored “improved to very much improved” in 93% of patients per the Global Aesthetic Improvement Scale, and 80% of the patients reported being “satisfied to extremely satisfied” with their aesthetic results.
Dr. Geronemus noted that, while it takes 2 to 7 days for wounds to close following ablative procedures, wounds close in about 10 minutes following microexcisional treatment, which possibly leads to faster healing of tissue. “Most people expect some downtime to achieve effective, long-lasting results,” he said. “The mean downtime was 3.8 days; 75% of subjects did not miss work, and 46% did not miss any social or leisure activities.”
To date, 79 subjects have been treated and a 90-day pivotal study is under way. Based on the clinical data to date, he said, “the new technique offers the ability to remove a significant amount of damaged, lax skin without concern of scarring or pigmentary change.”
Dr. Geronemus reported having served on the advisory board or as an investigator for Cynosure, Syneron Candela, Cutera, Revance Therapeutics, Allergan, Cytrellis Biosystems, the New York Stem Cell Foundation, among others. He also holds ownership interests with Cytrellis, the company that developed the coring device.
[email protected]
DALLAS – according to preliminary results from an ongoing study.
“This differs from laser treatment in the sense that there’s no thermal injury and it takes a deep core approach, along the lines of what you might expect from a punch biopsy,” lead study author Roy G. Geronemus, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “The device causes microscale excisions below the size that causes scar. It’s mechanical only, without the use of any thermal energy. There is quantitative and directional reduction in area of skin. This leads to wrinkle improvement, tightening, smoothing of lax skin, and skin rejuvenation.”
The average age of subjects was 64 years, and all had Fitzpatrick types II or III skin. No unanticipated adverse events or serious adverse events were observed, and histology from 3 subjects showed an excellent healing profile and no scarring. The average pain during treatment was 0.36 on the 0-10 Wong-Baker scale.
Interim 90-day data demonstrated that 87% of 30 cheek areas had 1, 2, or 3 levels of improvement in moderate to severe cheek wrinkles on the Lemperle scale, according to primary investigator assessment. Investigators and subjects scored “improved to very much improved” in 93% of patients per the Global Aesthetic Improvement Scale, and 80% of the patients reported being “satisfied to extremely satisfied” with their aesthetic results.
Dr. Geronemus noted that, while it takes 2 to 7 days for wounds to close following ablative procedures, wounds close in about 10 minutes following microexcisional treatment, which possibly leads to faster healing of tissue. “Most people expect some downtime to achieve effective, long-lasting results,” he said. “The mean downtime was 3.8 days; 75% of subjects did not miss work, and 46% did not miss any social or leisure activities.”
To date, 79 subjects have been treated and a 90-day pivotal study is under way. Based on the clinical data to date, he said, “the new technique offers the ability to remove a significant amount of damaged, lax skin without concern of scarring or pigmentary change.”
Dr. Geronemus reported having served on the advisory board or as an investigator for Cynosure, Syneron Candela, Cutera, Revance Therapeutics, Allergan, Cytrellis Biosystems, the New York Stem Cell Foundation, among others. He also holds ownership interests with Cytrellis, the company that developed the coring device.
[email protected]
REPORTING FROM ASLMS 2018
Key clinical point: A novel dermal microexcisional device has been designed to perform facial rejuvenation without the use of thermal energy.
Major finding: Interim 90-day data demonstrated that 87% of 30 cheek areas had 1, 2, or 3 levels of improvement in moderate to severe cheek wrinkles on the Lemperle scale.Study details: A multicenter study of 23 women who were treated bilaterally in the mid- to lower face with the 22-gauge coring device.
Disclosures: Dr. Geronemus reported having served on the advisory board or as an investigator for Cynosure, Syneron Candela, Cutera, Revance Therapeutics, Allergan, Cytrellis Biosystems, the New York Stem Cell Foundation, among others. He also holds ownership interests with Cytrellis.
Low incidence of HS in children does not diminish importance of early diagnosis
a study has found.
“The relatively low disease burden must not overshadow the extreme quality of life impact this disease has on those afflicted with it,” noted Amit Garg, MD, and associates at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hyde Park, N.Y.
The clinical term “hidradenitis’ was used to locate pediatric patients within a multi-institutional database of 55 million patients participating in 27 integrated health care organizations whose records were active in the database between March 2014 and March 2017.
The standardized prevalence of HS among girls was 3.75 times greater than in boys (P less than .0001), and the condition was most common in those aged 15-17 years (72%) across each racial group. “HS disproportionately affects African American children and adolescents, who have a 3.5-fold greater standardized prevalence than do Caucasians,” the authors wrote. The report was published in the Journal of Investigative Dermatology. Specifically, the highest prevalence by race was found in females aged 15-17 years who were African American (525 per 100,000) and biracial (253 per 100,000).
The authors acknowledged the availability of limited existing HS pediatric data from case reports and small series, none of which provided descriptions of subgroups by gender, age, or race.
In their review of the existing literature, Dr. Garg and his associates noted several key observations that may further aid in clinical diagnosis of pediatric patients at greater risk of developing HS:
- HS appears most likely to be a post-adrenarche disease; children with the disease more frequently present with a hormonal imbalance compared with adults. In fact, HS in children may be a marker of precocious puberty, as noted in those presenting with adrenal hyperplasia and premature adrenarche.
- A separate population-based analysis revealed an association between HS and polycystic ovary syndrome.
- Pediatric patients diagnosed with HS are more likely to present with a family history of the condition, and those experiencing early onset appear likely to develop more widespread HS.
- A fivefold likelihood of HS in pediatric Down syndrome patients is also attributed to genetic mutations.
The higher incidence of HS among adults (0.1%) is likely due to largely postpubertal disease onset, the authors speculated. They acknowledged that delays in diagnosing adolescent HS could account for the difference in prevalence between pediatric and adult populations. According to one study cited by Dr. Garg and his colleagues, adults with HS may have symptoms as many as 7 years prior to receiving a diagnosis.
Findings in Dr. Garg’s study serve to reinforce those of previous studies on adult HS populations, which also cited higher prevalence among females, especially African American females.
The research was funded by an unrestricted educational grant from AbbVie. Dr. Garg has served as an adviser for and received honoraria from AbbVie; the remaining researchers had no relevant financial disclosures.
SOURCE: Garg A et al. J Investig Dermatol. 2018 Apr 2. doi: 10.1016/j.jid.2018.04.001.
a study has found.
“The relatively low disease burden must not overshadow the extreme quality of life impact this disease has on those afflicted with it,” noted Amit Garg, MD, and associates at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hyde Park, N.Y.
The clinical term “hidradenitis’ was used to locate pediatric patients within a multi-institutional database of 55 million patients participating in 27 integrated health care organizations whose records were active in the database between March 2014 and March 2017.
The standardized prevalence of HS among girls was 3.75 times greater than in boys (P less than .0001), and the condition was most common in those aged 15-17 years (72%) across each racial group. “HS disproportionately affects African American children and adolescents, who have a 3.5-fold greater standardized prevalence than do Caucasians,” the authors wrote. The report was published in the Journal of Investigative Dermatology. Specifically, the highest prevalence by race was found in females aged 15-17 years who were African American (525 per 100,000) and biracial (253 per 100,000).
The authors acknowledged the availability of limited existing HS pediatric data from case reports and small series, none of which provided descriptions of subgroups by gender, age, or race.
In their review of the existing literature, Dr. Garg and his associates noted several key observations that may further aid in clinical diagnosis of pediatric patients at greater risk of developing HS:
- HS appears most likely to be a post-adrenarche disease; children with the disease more frequently present with a hormonal imbalance compared with adults. In fact, HS in children may be a marker of precocious puberty, as noted in those presenting with adrenal hyperplasia and premature adrenarche.
- A separate population-based analysis revealed an association between HS and polycystic ovary syndrome.
- Pediatric patients diagnosed with HS are more likely to present with a family history of the condition, and those experiencing early onset appear likely to develop more widespread HS.
- A fivefold likelihood of HS in pediatric Down syndrome patients is also attributed to genetic mutations.
The higher incidence of HS among adults (0.1%) is likely due to largely postpubertal disease onset, the authors speculated. They acknowledged that delays in diagnosing adolescent HS could account for the difference in prevalence between pediatric and adult populations. According to one study cited by Dr. Garg and his colleagues, adults with HS may have symptoms as many as 7 years prior to receiving a diagnosis.
Findings in Dr. Garg’s study serve to reinforce those of previous studies on adult HS populations, which also cited higher prevalence among females, especially African American females.
The research was funded by an unrestricted educational grant from AbbVie. Dr. Garg has served as an adviser for and received honoraria from AbbVie; the remaining researchers had no relevant financial disclosures.
SOURCE: Garg A et al. J Investig Dermatol. 2018 Apr 2. doi: 10.1016/j.jid.2018.04.001.
a study has found.
“The relatively low disease burden must not overshadow the extreme quality of life impact this disease has on those afflicted with it,” noted Amit Garg, MD, and associates at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hyde Park, N.Y.
The clinical term “hidradenitis’ was used to locate pediatric patients within a multi-institutional database of 55 million patients participating in 27 integrated health care organizations whose records were active in the database between March 2014 and March 2017.
The standardized prevalence of HS among girls was 3.75 times greater than in boys (P less than .0001), and the condition was most common in those aged 15-17 years (72%) across each racial group. “HS disproportionately affects African American children and adolescents, who have a 3.5-fold greater standardized prevalence than do Caucasians,” the authors wrote. The report was published in the Journal of Investigative Dermatology. Specifically, the highest prevalence by race was found in females aged 15-17 years who were African American (525 per 100,000) and biracial (253 per 100,000).
The authors acknowledged the availability of limited existing HS pediatric data from case reports and small series, none of which provided descriptions of subgroups by gender, age, or race.
In their review of the existing literature, Dr. Garg and his associates noted several key observations that may further aid in clinical diagnosis of pediatric patients at greater risk of developing HS:
- HS appears most likely to be a post-adrenarche disease; children with the disease more frequently present with a hormonal imbalance compared with adults. In fact, HS in children may be a marker of precocious puberty, as noted in those presenting with adrenal hyperplasia and premature adrenarche.
- A separate population-based analysis revealed an association between HS and polycystic ovary syndrome.
- Pediatric patients diagnosed with HS are more likely to present with a family history of the condition, and those experiencing early onset appear likely to develop more widespread HS.
- A fivefold likelihood of HS in pediatric Down syndrome patients is also attributed to genetic mutations.
The higher incidence of HS among adults (0.1%) is likely due to largely postpubertal disease onset, the authors speculated. They acknowledged that delays in diagnosing adolescent HS could account for the difference in prevalence between pediatric and adult populations. According to one study cited by Dr. Garg and his colleagues, adults with HS may have symptoms as many as 7 years prior to receiving a diagnosis.
Findings in Dr. Garg’s study serve to reinforce those of previous studies on adult HS populations, which also cited higher prevalence among females, especially African American females.
The research was funded by an unrestricted educational grant from AbbVie. Dr. Garg has served as an adviser for and received honoraria from AbbVie; the remaining researchers had no relevant financial disclosures.
SOURCE: Garg A et al. J Investig Dermatol. 2018 Apr 2. doi: 10.1016/j.jid.2018.04.001.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point: Onset of HS prior to age 10 years is extremely rate; more than two-thirds of cases occurred in teens aged 15-17 years.
Major finding: HS rates among girls are almost four times higher than those of boys; more than 70% of cases occurred in teens aged 15-17 years.
Study details: Cross-sectional population analysis of 1,240 pediatric patients sampled from a database of 55 million unique records.
Disclosures: The research was funded by an unrestricted educational grant from AbbVie. Dr. Garg has served as an adviser for and received honoraria from AbbVie; the remaining researchers had no relevant financial disclosures.
Source: Garg A et al. J Invest Dermatol. 2018 Apr 2. doi: 10.1016/j.jid.2018.04.001.
LRRK2 Mutation Is Associated With Slower Motor Decline in Parkinson’s Disease
The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is associated with slower motor function decline in Parkinson’s disease, according to data published in the March 1 issue of JAMA Neurology.
“Our findings of a slower decrease in motor Unified Parkinson’s Disease Rating Scale [UPDRS] score remained consistent even in sensitivity analyses that included only individuals who had two or more visits,” said Rachel Saunders-Pullman, MD, MPH, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City. “The slower progression estimates could inform clinical trial design for emerging LRRK2-targeted agents.”
A cross-sectional study suggested that Parkinson’s disease associated with LRRK2 G2019S mutation among patients of Ashkenazi Jewish descent is milder and may progress more slowly, compared with idiopathic Parkinson’s disease. To determine whether the longitudinal course of Parkinson’s disease in patients with the LRRK2 mutation differs from that in patients without the mutation, Dr. Saunders-Pullman and colleagues conducted a prospective, comprehensive assessment of patients from July 21, 2009, to September 30, 2016.
Researchers recruited participants of Ashkenazi Jewish ancestry with LRRK2-associated Parkinson’s disease or with idiopathic Parkinson’s disease from three sites. The investigators evaluated 545 participants who had one to four study visits. Patients with the glucocerebrosidase 1 (GBA1) mutation were excluded from the analysis.
The investigators used linear mixed-effects models for longitudinal motor scores to examine the association of LRRK2 mutation status with the rate of change in UPDRS III scores. They used disease duration as the time scale and adjusted the data for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. The researchers also used mixed-effects models to assess change in cognition, as measured by Montreal Cognitive Assessment scores.
Of the 545 participants, 233 were women. The mean age of patients with the LRRK2 mutation was 68.2, and the mean age of those without the mutation was 67.8. Seventy-two of the 144 participants with the LRRK2 mutation and 161 of the 401 participants with no mutation were women. Among patients with the LRRK2 mutation, the estimated rate of change in the UPDRS III motor score per year was lower (0.689 points/year), compared with those without the mutation (1.056 points/year).
“The present study is the first, to our knowledge, to demonstrate this milder progression using prospective analysis,” said Dr. Saunders-Pullman and colleagues. “It is unclear whether the overall milder course represents an average of divergent LRRK2 pathologic findings or less overall synuclein burden.
“Larger and longer-duration longitudinal studies, including those evaluating pathologic findings and nonmotor features, are warranted,” the researchers concluded.
—Erica Tricarico
Suggested Reading
Saunders-Pullman R, Mirelman A, Alcalay RN, et al. Progression in the LRRK2-associated Parkinson’s disease population. JAMA Neurol. 2018;75(3):312-319.
The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is associated with slower motor function decline in Parkinson’s disease, according to data published in the March 1 issue of JAMA Neurology.
“Our findings of a slower decrease in motor Unified Parkinson’s Disease Rating Scale [UPDRS] score remained consistent even in sensitivity analyses that included only individuals who had two or more visits,” said Rachel Saunders-Pullman, MD, MPH, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City. “The slower progression estimates could inform clinical trial design for emerging LRRK2-targeted agents.”
A cross-sectional study suggested that Parkinson’s disease associated with LRRK2 G2019S mutation among patients of Ashkenazi Jewish descent is milder and may progress more slowly, compared with idiopathic Parkinson’s disease. To determine whether the longitudinal course of Parkinson’s disease in patients with the LRRK2 mutation differs from that in patients without the mutation, Dr. Saunders-Pullman and colleagues conducted a prospective, comprehensive assessment of patients from July 21, 2009, to September 30, 2016.
Researchers recruited participants of Ashkenazi Jewish ancestry with LRRK2-associated Parkinson’s disease or with idiopathic Parkinson’s disease from three sites. The investigators evaluated 545 participants who had one to four study visits. Patients with the glucocerebrosidase 1 (GBA1) mutation were excluded from the analysis.
The investigators used linear mixed-effects models for longitudinal motor scores to examine the association of LRRK2 mutation status with the rate of change in UPDRS III scores. They used disease duration as the time scale and adjusted the data for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. The researchers also used mixed-effects models to assess change in cognition, as measured by Montreal Cognitive Assessment scores.
Of the 545 participants, 233 were women. The mean age of patients with the LRRK2 mutation was 68.2, and the mean age of those without the mutation was 67.8. Seventy-two of the 144 participants with the LRRK2 mutation and 161 of the 401 participants with no mutation were women. Among patients with the LRRK2 mutation, the estimated rate of change in the UPDRS III motor score per year was lower (0.689 points/year), compared with those without the mutation (1.056 points/year).
“The present study is the first, to our knowledge, to demonstrate this milder progression using prospective analysis,” said Dr. Saunders-Pullman and colleagues. “It is unclear whether the overall milder course represents an average of divergent LRRK2 pathologic findings or less overall synuclein burden.
“Larger and longer-duration longitudinal studies, including those evaluating pathologic findings and nonmotor features, are warranted,” the researchers concluded.
—Erica Tricarico
Suggested Reading
Saunders-Pullman R, Mirelman A, Alcalay RN, et al. Progression in the LRRK2-associated Parkinson’s disease population. JAMA Neurol. 2018;75(3):312-319.
The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is associated with slower motor function decline in Parkinson’s disease, according to data published in the March 1 issue of JAMA Neurology.
“Our findings of a slower decrease in motor Unified Parkinson’s Disease Rating Scale [UPDRS] score remained consistent even in sensitivity analyses that included only individuals who had two or more visits,” said Rachel Saunders-Pullman, MD, MPH, Associate Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City. “The slower progression estimates could inform clinical trial design for emerging LRRK2-targeted agents.”
A cross-sectional study suggested that Parkinson’s disease associated with LRRK2 G2019S mutation among patients of Ashkenazi Jewish descent is milder and may progress more slowly, compared with idiopathic Parkinson’s disease. To determine whether the longitudinal course of Parkinson’s disease in patients with the LRRK2 mutation differs from that in patients without the mutation, Dr. Saunders-Pullman and colleagues conducted a prospective, comprehensive assessment of patients from July 21, 2009, to September 30, 2016.
Researchers recruited participants of Ashkenazi Jewish ancestry with LRRK2-associated Parkinson’s disease or with idiopathic Parkinson’s disease from three sites. The investigators evaluated 545 participants who had one to four study visits. Patients with the glucocerebrosidase 1 (GBA1) mutation were excluded from the analysis.
The investigators used linear mixed-effects models for longitudinal motor scores to examine the association of LRRK2 mutation status with the rate of change in UPDRS III scores. They used disease duration as the time scale and adjusted the data for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. The researchers also used mixed-effects models to assess change in cognition, as measured by Montreal Cognitive Assessment scores.
Of the 545 participants, 233 were women. The mean age of patients with the LRRK2 mutation was 68.2, and the mean age of those without the mutation was 67.8. Seventy-two of the 144 participants with the LRRK2 mutation and 161 of the 401 participants with no mutation were women. Among patients with the LRRK2 mutation, the estimated rate of change in the UPDRS III motor score per year was lower (0.689 points/year), compared with those without the mutation (1.056 points/year).
“The present study is the first, to our knowledge, to demonstrate this milder progression using prospective analysis,” said Dr. Saunders-Pullman and colleagues. “It is unclear whether the overall milder course represents an average of divergent LRRK2 pathologic findings or less overall synuclein burden.
“Larger and longer-duration longitudinal studies, including those evaluating pathologic findings and nonmotor features, are warranted,” the researchers concluded.
—Erica Tricarico
Suggested Reading
Saunders-Pullman R, Mirelman A, Alcalay RN, et al. Progression in the LRRK2-associated Parkinson’s disease population. JAMA Neurol. 2018;75(3):312-319.
Stroke-smoking link is dose dependent in young men
In men younger than 50 years, even just a reduction in the number of cigarettes smoked may decrease the risk of ischemic stroke, according to a population-based, case-control study.
The odds ratio for a stroke was 1.21 for men who smoked fewer than 11 cigarettes per day, compared with nonsmokers, and 5.24 for those who smoked 40 or more per day, reported Janina Markidan and her coinvestigators in Stroke.
A prior study showed a similar relationship in young women, but the researchers decided to conduct a follow-up study in men in order to eliminate hormonal confounders (Stroke. 2008 Sep;39[9]:2439-43).
Ms. Markidan and her colleagues used data from the Stroke Prevention in Young Men Study, which recruited 615 men who had experienced a stroke in the previous three years, and compared these men with 530 age-, ethnicity-, and geography-matched controls.
There were some statistically significant differences in the two populations: Cases had lower levels of education and had greater incidences of hypertension, diabetes, myocardial infarction, angina, and obesity (all P < .05).
Current smokers were identified as those who had smoked more than 100 cigarettes in their lifetime and who had smoked a cigarette in the 30 days preceding the stroke. Never smokers were those who had smoked fewer than 100 cigarettes in their lifetime or who had never smoked five packs.
Compared with never smokers, current smokers had an odds ratio for stroke of 1.88 (95% confidence interval, 1.44-2.44). When the researchers stratified smokers by the number of cigarettes smoked, the stroke risk appeared to be dose dependent in the fully adjusted models: The OR for 1-10 cigarettes/day was 1.21 (95% CI, 0.83-1.77), 1.64 for 11-20 cigarettes/day (95% CI, 1.10-2.43), 3.51 for 21-39 cigarettes/day (95% CI, 1.65-7.45), and 5.24 for 40 or more cigarettes/day (95% CI, 1.90-14.42).
The study cannot prove causation and did not include smoking of nontobacco products, alcohol consumption, or physical activity.
“While complete cessation of smoking is the goal, even reducing the number of cigarettes smoked may have beneficial health effects,” wrote Ms. Markidan, a medical student at the University of Maryland, Baltimore, and her colleagues.
SOURCE: Markidan J et al. Stroke. 2018 May;49(5):1276-8.
In men younger than 50 years, even just a reduction in the number of cigarettes smoked may decrease the risk of ischemic stroke, according to a population-based, case-control study.
The odds ratio for a stroke was 1.21 for men who smoked fewer than 11 cigarettes per day, compared with nonsmokers, and 5.24 for those who smoked 40 or more per day, reported Janina Markidan and her coinvestigators in Stroke.
A prior study showed a similar relationship in young women, but the researchers decided to conduct a follow-up study in men in order to eliminate hormonal confounders (Stroke. 2008 Sep;39[9]:2439-43).
Ms. Markidan and her colleagues used data from the Stroke Prevention in Young Men Study, which recruited 615 men who had experienced a stroke in the previous three years, and compared these men with 530 age-, ethnicity-, and geography-matched controls.
There were some statistically significant differences in the two populations: Cases had lower levels of education and had greater incidences of hypertension, diabetes, myocardial infarction, angina, and obesity (all P < .05).
Current smokers were identified as those who had smoked more than 100 cigarettes in their lifetime and who had smoked a cigarette in the 30 days preceding the stroke. Never smokers were those who had smoked fewer than 100 cigarettes in their lifetime or who had never smoked five packs.
Compared with never smokers, current smokers had an odds ratio for stroke of 1.88 (95% confidence interval, 1.44-2.44). When the researchers stratified smokers by the number of cigarettes smoked, the stroke risk appeared to be dose dependent in the fully adjusted models: The OR for 1-10 cigarettes/day was 1.21 (95% CI, 0.83-1.77), 1.64 for 11-20 cigarettes/day (95% CI, 1.10-2.43), 3.51 for 21-39 cigarettes/day (95% CI, 1.65-7.45), and 5.24 for 40 or more cigarettes/day (95% CI, 1.90-14.42).
The study cannot prove causation and did not include smoking of nontobacco products, alcohol consumption, or physical activity.
“While complete cessation of smoking is the goal, even reducing the number of cigarettes smoked may have beneficial health effects,” wrote Ms. Markidan, a medical student at the University of Maryland, Baltimore, and her colleagues.
SOURCE: Markidan J et al. Stroke. 2018 May;49(5):1276-8.
In men younger than 50 years, even just a reduction in the number of cigarettes smoked may decrease the risk of ischemic stroke, according to a population-based, case-control study.
The odds ratio for a stroke was 1.21 for men who smoked fewer than 11 cigarettes per day, compared with nonsmokers, and 5.24 for those who smoked 40 or more per day, reported Janina Markidan and her coinvestigators in Stroke.
A prior study showed a similar relationship in young women, but the researchers decided to conduct a follow-up study in men in order to eliminate hormonal confounders (Stroke. 2008 Sep;39[9]:2439-43).
Ms. Markidan and her colleagues used data from the Stroke Prevention in Young Men Study, which recruited 615 men who had experienced a stroke in the previous three years, and compared these men with 530 age-, ethnicity-, and geography-matched controls.
There were some statistically significant differences in the two populations: Cases had lower levels of education and had greater incidences of hypertension, diabetes, myocardial infarction, angina, and obesity (all P < .05).
Current smokers were identified as those who had smoked more than 100 cigarettes in their lifetime and who had smoked a cigarette in the 30 days preceding the stroke. Never smokers were those who had smoked fewer than 100 cigarettes in their lifetime or who had never smoked five packs.
Compared with never smokers, current smokers had an odds ratio for stroke of 1.88 (95% confidence interval, 1.44-2.44). When the researchers stratified smokers by the number of cigarettes smoked, the stroke risk appeared to be dose dependent in the fully adjusted models: The OR for 1-10 cigarettes/day was 1.21 (95% CI, 0.83-1.77), 1.64 for 11-20 cigarettes/day (95% CI, 1.10-2.43), 3.51 for 21-39 cigarettes/day (95% CI, 1.65-7.45), and 5.24 for 40 or more cigarettes/day (95% CI, 1.90-14.42).
The study cannot prove causation and did not include smoking of nontobacco products, alcohol consumption, or physical activity.
“While complete cessation of smoking is the goal, even reducing the number of cigarettes smoked may have beneficial health effects,” wrote Ms. Markidan, a medical student at the University of Maryland, Baltimore, and her colleagues.
SOURCE: Markidan J et al. Stroke. 2018 May;49(5):1276-8.
FROM STROKE
Key clinical point:
Major finding: The odds ratio for stroke ranged from 1.21 to 5.24 with increased smoking.
Study details: Case-controlled study of 1,145 stroke patients and controls.
Disclosures: The study was funded by the Department of Veterans Affairs, the Centers for Disease Control and Prevention, and the National Institutes of Health. The authors declared no relevant financial relationships.
Source: Markidan J et al. Stroke. 2018 May;49(5):1276-8.
FDA begins priority review of cemiplimab for advanced cutaneous squamous cell carcinoma
The Food and Drug Administration will conduct a priority review of cemiplimab for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (SCC), the companies developing the treatment announced on April 30.
Cemiplimab, a human monoclonal antibody being developed by Regeneron Pharmaceuticals and Sanofi, targets the checkpoint inhibitor programmed cell death protein-1 (PD-1). The drug was previously granted Breakthrough Therapy status by the FDA in September 2017.
No safety and efficacy data are available for cemiplimab at this time.
Find the full press release on the Regeneron website.
The Food and Drug Administration will conduct a priority review of cemiplimab for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (SCC), the companies developing the treatment announced on April 30.
Cemiplimab, a human monoclonal antibody being developed by Regeneron Pharmaceuticals and Sanofi, targets the checkpoint inhibitor programmed cell death protein-1 (PD-1). The drug was previously granted Breakthrough Therapy status by the FDA in September 2017.
No safety and efficacy data are available for cemiplimab at this time.
Find the full press release on the Regeneron website.
The Food and Drug Administration will conduct a priority review of cemiplimab for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (SCC), the companies developing the treatment announced on April 30.
Cemiplimab, a human monoclonal antibody being developed by Regeneron Pharmaceuticals and Sanofi, targets the checkpoint inhibitor programmed cell death protein-1 (PD-1). The drug was previously granted Breakthrough Therapy status by the FDA in September 2017.
No safety and efficacy data are available for cemiplimab at this time.
Find the full press release on the Regeneron website.
Consider caregiver oral health for children with bleeding disorders
SAN DIEGO – Caregiver oral health status is an identifiable risk factor that could be used to screen for poor oral health among children and young adults with bleeding disorders, results from a single-center suggest.
“We ask parents one simple question: ‘Have you had a cavity in the last year?’ If they say yes, we would be more concerned that their children would be more likely to have poor oral health,” Elizabeth Hastie said in an interview during a poster session at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
Proper oral health may prevent joint disease and other conditions that predispose patients to bleeds, according to Ms. Hastie, a fourth-year medical student at Emory University, Atlanta. However, of the 147 hemophilia treatment centers in the United States, just 30% have a dentist on staff, while 90% of centers have expressed interest in increasing patient education in oral health.
In an effort to evaluate the dental habits, needs, and oral health issues of children and young adults up to age 18 with bleeding disorders, Ms. Hastie and her associates conducted a cross-sectional study of 226 patients who were evaluated by a staff dental hygienist at Children’s Healthcare of Atlanta Comprehensive Bleeding Disorders Clinic from May 2016 to October 2017.
The evaluation consisted of a 14-question survey derived from the American Academy of Pediatric Dentistry Caries–Risk Assessment Tool completed by the primary caregiver present during the visit and oral screening. The researchers extracted demographic and clinical characteristics from the patient’s chart and included age, race, county of residence, and bleeding disorder type and severity.
Nearly half of the patients (44%) reported they did not brush their teeth twice a day. Children younger than age 5 years were more likely to not brush their teeth twice a day, compared with children aged 5-14 years and young adults aged 15-18 years (57% vs. 44% and 31% respectively, P = .08).
More than one-quarter of patients (27%) reported not having a current dentist and 15% reported specific challenges with access to dental care including burdens related to distance, insurance coverage, and finding a provider willing to treat in the setting of their medical condition. Those who were Medicaid eligible or of low socioeconomic status were significantly more likely to report dental care access issues, compared with other patients (20% vs. 9%; P = .01).
Oral screening performed by the dental hygienist demonstrated significant oral pathology: 89% of patients had plaque accumulation, 57% had white spots or decalcifications, 37% had gingivitis, and 8% had suspicious lesions suggestive of dental caries.
The researchers also found that having a caregiver with active oral disease in the past 12 months increased the odds of suspicious lesions (odds ratio, 4.34), increased the odds of gingivitis (OR, 3.80), and decreased the odds of the patients’ brushing their teeth at least twice per day (OR, 0.17).
“Hopefully, if we can target those high-risk patients in clinic, we could reduce costs, the number of bleeds, the number of products and factor used, and potentially even morbidity in the future,” Ms. Hastie said.
She acknowledged certain limitations of the study, including its single-center design and the fact that a dental hygienist performed the majority of evaluations. She reported having no financial disclosures.
SAN DIEGO – Caregiver oral health status is an identifiable risk factor that could be used to screen for poor oral health among children and young adults with bleeding disorders, results from a single-center suggest.
“We ask parents one simple question: ‘Have you had a cavity in the last year?’ If they say yes, we would be more concerned that their children would be more likely to have poor oral health,” Elizabeth Hastie said in an interview during a poster session at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
Proper oral health may prevent joint disease and other conditions that predispose patients to bleeds, according to Ms. Hastie, a fourth-year medical student at Emory University, Atlanta. However, of the 147 hemophilia treatment centers in the United States, just 30% have a dentist on staff, while 90% of centers have expressed interest in increasing patient education in oral health.
In an effort to evaluate the dental habits, needs, and oral health issues of children and young adults up to age 18 with bleeding disorders, Ms. Hastie and her associates conducted a cross-sectional study of 226 patients who were evaluated by a staff dental hygienist at Children’s Healthcare of Atlanta Comprehensive Bleeding Disorders Clinic from May 2016 to October 2017.
The evaluation consisted of a 14-question survey derived from the American Academy of Pediatric Dentistry Caries–Risk Assessment Tool completed by the primary caregiver present during the visit and oral screening. The researchers extracted demographic and clinical characteristics from the patient’s chart and included age, race, county of residence, and bleeding disorder type and severity.
Nearly half of the patients (44%) reported they did not brush their teeth twice a day. Children younger than age 5 years were more likely to not brush their teeth twice a day, compared with children aged 5-14 years and young adults aged 15-18 years (57% vs. 44% and 31% respectively, P = .08).
More than one-quarter of patients (27%) reported not having a current dentist and 15% reported specific challenges with access to dental care including burdens related to distance, insurance coverage, and finding a provider willing to treat in the setting of their medical condition. Those who were Medicaid eligible or of low socioeconomic status were significantly more likely to report dental care access issues, compared with other patients (20% vs. 9%; P = .01).
Oral screening performed by the dental hygienist demonstrated significant oral pathology: 89% of patients had plaque accumulation, 57% had white spots or decalcifications, 37% had gingivitis, and 8% had suspicious lesions suggestive of dental caries.
The researchers also found that having a caregiver with active oral disease in the past 12 months increased the odds of suspicious lesions (odds ratio, 4.34), increased the odds of gingivitis (OR, 3.80), and decreased the odds of the patients’ brushing their teeth at least twice per day (OR, 0.17).
“Hopefully, if we can target those high-risk patients in clinic, we could reduce costs, the number of bleeds, the number of products and factor used, and potentially even morbidity in the future,” Ms. Hastie said.
She acknowledged certain limitations of the study, including its single-center design and the fact that a dental hygienist performed the majority of evaluations. She reported having no financial disclosures.
SAN DIEGO – Caregiver oral health status is an identifiable risk factor that could be used to screen for poor oral health among children and young adults with bleeding disorders, results from a single-center suggest.
“We ask parents one simple question: ‘Have you had a cavity in the last year?’ If they say yes, we would be more concerned that their children would be more likely to have poor oral health,” Elizabeth Hastie said in an interview during a poster session at the biennial summit of the Thrombosis & Hemostasis Societies of North America.
Proper oral health may prevent joint disease and other conditions that predispose patients to bleeds, according to Ms. Hastie, a fourth-year medical student at Emory University, Atlanta. However, of the 147 hemophilia treatment centers in the United States, just 30% have a dentist on staff, while 90% of centers have expressed interest in increasing patient education in oral health.
In an effort to evaluate the dental habits, needs, and oral health issues of children and young adults up to age 18 with bleeding disorders, Ms. Hastie and her associates conducted a cross-sectional study of 226 patients who were evaluated by a staff dental hygienist at Children’s Healthcare of Atlanta Comprehensive Bleeding Disorders Clinic from May 2016 to October 2017.
The evaluation consisted of a 14-question survey derived from the American Academy of Pediatric Dentistry Caries–Risk Assessment Tool completed by the primary caregiver present during the visit and oral screening. The researchers extracted demographic and clinical characteristics from the patient’s chart and included age, race, county of residence, and bleeding disorder type and severity.
Nearly half of the patients (44%) reported they did not brush their teeth twice a day. Children younger than age 5 years were more likely to not brush their teeth twice a day, compared with children aged 5-14 years and young adults aged 15-18 years (57% vs. 44% and 31% respectively, P = .08).
More than one-quarter of patients (27%) reported not having a current dentist and 15% reported specific challenges with access to dental care including burdens related to distance, insurance coverage, and finding a provider willing to treat in the setting of their medical condition. Those who were Medicaid eligible or of low socioeconomic status were significantly more likely to report dental care access issues, compared with other patients (20% vs. 9%; P = .01).
Oral screening performed by the dental hygienist demonstrated significant oral pathology: 89% of patients had plaque accumulation, 57% had white spots or decalcifications, 37% had gingivitis, and 8% had suspicious lesions suggestive of dental caries.
The researchers also found that having a caregiver with active oral disease in the past 12 months increased the odds of suspicious lesions (odds ratio, 4.34), increased the odds of gingivitis (OR, 3.80), and decreased the odds of the patients’ brushing their teeth at least twice per day (OR, 0.17).
“Hopefully, if we can target those high-risk patients in clinic, we could reduce costs, the number of bleeds, the number of products and factor used, and potentially even morbidity in the future,” Ms. Hastie said.
She acknowledged certain limitations of the study, including its single-center design and the fact that a dental hygienist performed the majority of evaluations. She reported having no financial disclosures.
REPORTING FROM THSNA 2018
Key clinical point:
Major finding: Having a caregiver with active oral disease in the past 12 months increased the odds of the child having a suspicious lesion (OR 4.34) and gingivitis (OR 3.80).
Study details: A cross-sectional study of 226 pediatric patients who were evaluated by a dental hygienist.
Disclosures: Ms. Hastie reported having no financial disclosures.
Source: Hastie E et al. THSNA 2018, Poster 150.
Genetic markers may help predict allogeneic SCT outcomes
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
SALT LAKE CITY – The presence of p2X7 receptor single nucleotide polymorphisms (SNPs) associated with gain and loss of function may help predict outcomes after allogeneic stem cell transplantation, according to findings from a clinical correlate analysis of recipient and donor DNA samples.
The findings require validation in future studies, but suggest that the presence of the SNPs and p2X7 haplotypes 2 and 4 could be incorporated into disease risk models to improve transplant decision making, David Stuart Ritchie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The analysis, which specifically looked for the presence of 16 previously identified SNPs and the haplotypes 2 and 4 in p2x7, was performed on pretransplant DNA samples from 333 allogeneic stem cell transplant recipients and 228 donors at a single center between 2002 and 2013. The findings were correlated with patient outcomes.
Five SNPs were excluded from correlation because of low frequency, and of the 11 remaining SNPs, 3 were found to be significantly associated with reduced incidence of acute and/or chronic graft-versus-host disease (GVHD), and 2 were significantly associated with increased relapse or transplant-related mortality, said Dr. Ritchie of the University of Melbourne, Parkville, Australia.
The loss-of-function SNPs rs28360457 and rs3751133 – each linked with decreased inflammation – were significantly associated with a reduced incidence of acute GVHD when comparing grade 0 with grades 1-4 GVHD (P = .0234 and P = .0411, respectively), but not when comparing grades 0-1 and grades 2-4 GVHD.
SNP rs3751133 was also significantly associated with reduced incidence of chronic GVHD when comparing grade 0 with grades 0-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD, he said.
The loss-of-function SNP rs1653624 – which is linked with decreased phagocytosis – was associated with an increased incidence of acute GVHD when comparing grade 0 vs. grade 1-4 GVHD (P = .01), but not when comparing grades 0-1 and grades 2-4 GVHD (P = NS).
SNP rs7958311, which had increased surface expression, was associated with a trend toward increased relapse risk (P = .053), and the loss-of-function SNP rs1653624 was associated with an excess of early transplant-related mortality (P = .0471).
“Individual SNPs are interesting, but perhaps more interesting are the haplotypes,” Dr. Ritchie said.
Haplotype 4, which was found in 8 recipients, involves rs1718119 and rs7958311. Those SNPs were previously shown to have 300% and 195% increased expression, respectively, with or without rs2230912, which has been shown to be decreased by 72%, and with or without loss of function rs1653624. Haplotype 4 is associated with a net increase in p2X7 activity, he explained.
In the current study, haplotype 4 was only found to involve rs1718119 co-inherited with rs2230912, and was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946), when compared with haplotype 2 (HR, 0.2078), he said.
The differences between haplotype 4 and haplotype 2, and between haplotype 4 and patients with neither haplotype, were highly statistically significant.
Relapse-free survival did not differ significantly between those with haplotype 2 and those with neither haplotype (HR, 0.7717). Similarly, overall survival was significantly poorer among those with haplotype 4 versus haplotype 2 or no haplotype (HR, 0.2812 and 0.2882, respectively), but no difference was seen in overall survival between those with haplotype 2 and those with no haplotype (HR, 1.003), he said.
P2X7 is a purinergic signaling receptor located at chromosome 12q24–a region associated with inflammatory disorders. It plays an important role in immunogenic cell death. It is expressed in all leukocytes, with the highest level of expression seen in monocyte lineage. Binding of its ligand – extracellular adenosine 5’-triphosphate – leads to activation of dendritic cells and release of IL1b leading to T cell recruitment and the production of memory T cells.
Both gain- and loss-of-function SNPs in p2X7 have been reported and implicated in GVHD and other inflammatory disorders, Dr. Ritchie said, explaining the rationale for studying their correlations with outcomes after allogeneic stem cell transplantation.
While such transplants are highly effective for treating hematologic malignancies, outcomes can be adversely affected by infection, acute organ dysfunction, and GVHD. Pretransplant conditioning regimens are associated with high levels of immunogenic cell death and the release of extracellular adenosine 5’-triphosphate, therefore signaling through the p2X7 receptor may lead to activation of downstream effectors that influence transplant outcome, he noted.
“We hypothesized that germline gain or loss of function polymorphisms in this receptor in recipients of allogeneic transplantation would result in an adverse outcome,” he said.
The mean age of the recipients whose samples were analyzed was 46 years, and about half were women. Most (83.8%) had a peripheral blood graft source and 64% of transplants were from related donors. The nonrelapse mortality at 24 months was 12.98%, Dr. Ritchie said, noting that their indications for transplantation were “fairly representative of the adult transplant population, dominated by acute leukemia with a range of other acute conditions.”
The findings – particularly those with respect to haplotype 4, which had the most substantial impact – could play a role in patient risk assessment.
“Potentially, although it is a relatively uncommon haplotype, pretransplant identification of haplotype 4 may well have implications for transplant decision making, given the fact that the majority of our patients with this haplotype did not survive posttransplant,” he concluded, noting that an effort to validate the findings is ongoing in an additional 300 patients.
Dr. Ritchie reported having no financial disclosures.
SOURCE: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Haplotype 4 was associated with substantially decreased relapse-free survival overall (hazard ratio, 0.6946) versus haplotype 2 (HR, 0.2078).
Study details: A clinical correlate analysis of 561 DNA samples.
Disclosures: Dr. Ritchie reported having no financial disclosures.
Source: Koldej R et al. The 2018 BMT Tandem Meetings, Abstract 22.
New options emerge for primary biliary cholangitis
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
Low Vitamin B12 Level Is Associated With Worsening in Parkinson’s Disease
People with early, untreated Parkinson’s disease who have low vitamin B12 levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression. 
Previous research revealed that low serum vitamin B12 levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.
An Analysis of the DATATOP Study
Because little is known about B12’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (ie, less than 184 pmol/L), and 5% had deficient B12 levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine.
Homocysteine Was Associated With Cognitive Outcomes
Low B12 at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B12 tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.
“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.
Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).
Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, mean annualized increase in B12 was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they added.
The researchers speculated that a link between low B12 levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” said Dr. Christine and colleagues.
Study Raises Questions
“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.
If vitamin B12 is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.
“First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B12 levels.
“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.
“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.”
Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B12 in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.
—Nicola Garrett
Cardoso F. Vitamin B12 and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].
Christine CW, Auinger P, Joslin A, et al. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].
People with early, untreated Parkinson’s disease who have low vitamin B12 levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.
Previous research revealed that low serum vitamin B12 levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.
An Analysis of the DATATOP Study
Because little is known about B12’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (ie, less than 184 pmol/L), and 5% had deficient B12 levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine.
Homocysteine Was Associated With Cognitive Outcomes
Low B12 at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B12 tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.
“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.
Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).
Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, mean annualized increase in B12 was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they added.
The researchers speculated that a link between low B12 levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” said Dr. Christine and colleagues.
Study Raises Questions
“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.
If vitamin B12 is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.
“First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B12 levels.
“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.
“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.”
Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B12 in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.
—Nicola Garrett
Cardoso F. Vitamin B12 and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].
Christine CW, Auinger P, Joslin A, et al. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].
People with early, untreated Parkinson’s disease who have low vitamin B12 levels appear to have greater worsening of mobility and cognitive decline over time, according to research published online ahead of print March 6 in Movement Disorders. The results suggest that correcting low levels may slow disease progression.
Previous research revealed that low serum vitamin B12 levels are common in patients with moderately advanced Parkinson’s disease and are associated with neuropathy and cognitive impairment. Investigators led by Chadwick W. Christine, MD, a neurologist at the University of California, San Francisco, sought to understand what contributes to variation in the progression of Parkinson’s disease.
An Analysis of the DATATOP Study
Because little is known about B12’s role in early disease, the investigators analyzed data from patients with early, untreated Parkinson’s disease who participated in the DATATOP study, a double-blind, randomized trial designed to test whether treatment with selegiline, the antioxidant alpha-tocopherol, or both slowed disease progression.
They measured serum methylmalonic acid, homocysteine, and holotranscobalamin in addition to B12 because of the limited sensitivity of serum B12 testing alone to detect B12 deficiency. At baseline, 13% of 680 patients had borderline-low B12 levels (ie, less than 184 pmol/L), and 5% had deficient B12 levels (ie, less than 157 pmol/L). Homocysteine was moderately elevated (ie, greater than 15 mmol/L) in 7% of subjects, and 14% of patients with borderline-low B12 also had elevated homocysteine.
Homocysteine Was Associated With Cognitive Outcomes
Low B12 at baseline predicted greater worsening of mobility, in terms of a higher ambulatory capacity score. Investigators calculated this score by adding the falling, freezing when walking, walking, gait, and postural stability scores of the Unified Parkinson’s Disease Rating Scale (UPDRS). Participants in the low-B12 tertile (ie, less than 234 pmol/L) developed greater morbidity, as assessed by greater annualized worsening of the ambulatory capacity score. Participants in the low-B12 tertile had annualized change of 1.53, compared with 0.77 in the upper tertile. The worsening score mostly resulted from poorer gait and postural instability.
“We consider the magnitude of difference to be clinically relevant, particularly given that components of gait dysfunction that develop in Parkinson’s disease may not respond to dopaminergic treatments or [deep brain stimulation],” said Dr. Christine and colleagues.
Elevated homocysteine predicted greater cognitive decline. Baseline elevated homocysteine was associated with lower baseline Mini-Mental State Examination (MMSE) score, as well as greater annualized decline in MMSE (–1.96 vs 0.06).
Of the 456 subjects who continued in the study for nine to 24 months and had a second blood sample available, 226 had an increase of more than 20% in B12 levels, 210 stayed within 20% of the original B12 measurement, and 19 had a decrease greater than 20%.
Overall, mean annualized increase in B12 was 52.6 pmol/L, mean annualized decrease of homocysteine was 0.83 mmol/L, and mean annualized increase of holotranscobalamin was 14.7 pmol/L.
“These findings are consistent with improved nutritional status during the course of the study, likely attributed to subjects starting the optional [multivitamin] after the baseline visit and/or subjects changing their diets,” said the investigators.
While the improvement in B12 status did not lead to statistically significant improvements in UPDRS scores, there was a trend toward improvement, which provides “support for a disease-modifying effect of B12,” they added.
The researchers speculated that a link between low B12 levels and worse outcomes could be attributed to an independent comorbid effect on the CNS and peripheral nervous system or a direct effect on Parkinson’s disease pathogenesis. Alternatively, low B12 may be a marker of an unknown associated factor.
“Given that low B12 status is associated with neurologic and other medical morbidities and is readily treated, great care would be needed to design an ethically acceptable randomized, prospective study to evaluate the effect of B12 supplementation on Parkinson’s disease progression, given that serum measurements collected as part of a prospective study in unsupplemented patients would likely reveal some subjects with B12 deficiency,” said Dr. Christine and colleagues.
Study Raises Questions
“The course of Parkinson’s disease can be quite variable, and it is difficult for clinicians to predict what will happen to an individual person with Parkinson’s disease, but identifying prognostic factors ought to help practitioners answer their patients’ questions and potentially improve the understanding of mechanisms underlying the disease pathogenesis,” said Francisco Cardoso, MD, PhD, Professor of Neurology at the Federal University of Minas Gerais in Belo Horizonte, Brazil, in an accompanying editorial.
If vitamin B12 is related to the progression of Parkinson’s disease, then replacing it may slow patients’ decline. But the findings raise questions that need to be addressed, said Dr. Cardoso.
“First, what constitutes a low vitamin B12 level is not a simple issue. If the evaluation is limited to measurement of vitamin B12 concentration, the diagnosis of genuine deficiency is unreliable. Most experts agree that combined measurement of vitamin B12 with determination of homocysteine levels is necessary, and while Christine et al measured both levels, their statistical analysis and subsequent conclusions are exclusively based on the levels of the vitamin.
“Moreover, 34 patients in the study were classified as having ‘borderline-low’ vitamin B12 levels, and 14 had both borderline-low B12 level and high homocysteine concentration. This brings into question whether the researchers identified Parkinson’s disease patients who actually had low B12 levels.
“The design of the DATATOP trial could also introduce some bias into the findings. At the time of publication, the study was criticized for disregarding the symptomatic effect of selegiline and for a lack of objective definition of criteria for the trial’s primary end point—introduction of levodopa.
“This could have led to the termination of individuals at different stages of the disease, introducing a potential bias in the sample of patients who remained in the study for enough time to undergo subsequent determination of B12 levels.”
Furthermore, the findings of Christine et al contrast with those of previous research. The underlying mechanism of vitamin B12 in Parkinson’s disease is unclear. “Nevertheless, the results of the study by Dr. Christine and his colleagues are intriguing, and further investigations to address this hypothesis are warranted,” Dr. Cardoso concluded.
—Nicola Garrett
Cardoso F. Vitamin B12 and Parkinson’s disease: What is the relationship? Mov Disord. 2018 Mar 6 [Epub ahead of print].
Christine CW, Auinger P, Joslin A, et al. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 Mar 6 [Epub ahead of print].