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How to limit radiation in endovascular procedures
CHICAGO – Applying the key principles for limiting radiation exposure for vascular surgeons and staff – not to mention patients – during endovascular procedures involves a thorough understanding of dose metrics as well as risk factors for high-dose interventions, according to recent findings reported at a symposium on vascular surgery sponsored by Northwestern University.
Melissa Kirkwood, MD, of the University of Texas Southwestern Medical Center in Dallas, reported on her institution’s experience with limiting radiation exposure in typically high-dose cases. “What we found was that even though we had a substantial amount of dose in these cases – they included a significant proportion of 5- to 10-Gy and greater than 10-Gy cases – there were still no skin injuries detected in these patients,” she said, referencing retrospective and prospective analyses (J Vasc Surg. 2014;60:742-8; J Vasc Surg. 2015;61:902-6).
Vigilance regarding these principles for vascular surgeons is paramount, Dr. Kirkwood said, noting that the National Council on Radiation Protection and Measurements threshold for substantial radiation dose is 5 Gy or greater. “When you’re doing complex endovascular work, your doses can get that high,” she said.
As a means of measuring dose, Dr. Kirkwood called fluoroscopy time a “universally poor indicator” because in current practice vascular surgeons use digital acquisition mode in addition to fluoroscopy. “The digital acquisitions generate 10-100 times more dose than fluoroscopy, so if you’re only looking at fluoroscopy time, your potentially missing the majority of the dose for that case,” she said.
More applicable dose measures, she said, are kerma area product that measures total radiation beam output from the x-ray tube, which she called “a better reflection of operator exposure,” and reference air kerma (RAK), a measure of the dose at a reference point 15 cm along the beam axis toward the focal spot from the isocenter, which she said is the best approximation for patient peak skin dose exposure. However, the latter does not account for angle of the x-ray tube or patient position, which can vary based on the type of procedure or the patient’s size.
Dr. Kirkwood’s work at UTSW also determined that operator exposure during an endovascular procedure depends on where they stand. “Doubling the distance from the source can decrease the radiation level by a factor of four,” she said. For femoral access in the right groin, the operator is at greatest risk for exposure followed by the assistant when the assistant is standing to the right of the operator. The left brachial access site carries an even higher exposure for the operator, she said.
The table-mounted lead skirt plays a key role in limiting operator exposure, Dr. Kirkwood said. “It can be cumbersome, but it is very important in lowering your lower-body dose,” she said, because it will block radiation scatter coming off the bottom of the table.
At UTSW, the endovascular operators had a tutorial with the staff medical physicist on best practices to limit radiation exposure. “What we found was that we were significantly able to decrease the dose across all cases by simply going over a few principles,” she said.
Among those principles: “Always be aware when you’re on the fluoroscopy pedal and always use the lowest fluoroscopy mode possible,” she said. However, she noted that in difficult-to-visualize cases, a short-duration boost in fluoroscopy level might reduce overall fluoroscopy time and hence limit exposure. To limit digital acquisition mode, the use of fluoroscopic looping can allow for review of images during the procedure with a fraction of the dose that would be needed for a digital acquisition run.
Limiting magnification and using collimation can be complementary, Dr. Kirkwood said. “If you really have to magnify to see the area of interest, make sure you have tight collimation to try to decrease the scatter to you and your colleagues in the OR,” she said.
Dr. Kirkwood noted that raising the angio table as high as is comfortable and decreasing the distance between the source and image detector can limit patient exposure. Operators should avoid steep angulations of the x-ray tube, she said, but when angulations are necessary, operators should stand on the opposite side of the x-ray tube. “The best operating practice if you know you’re going to have a high-dose case with a lot of gantry angulation would be to tightly collimate to the area of interest and minimize the magnification,” she said.
Though not necessarily a principle, keeping up with software advances for imaging devices can also prove valuable for limiting radiation exposure, Dr. Kirkwood said. “It’s important to know about them because if you are purchasing new equipment, they are not necessarily included if you’re institution is looking to hold down costs,” she said.
Dr. Kirkwood had no relevant financial disclosures.
CHICAGO – Applying the key principles for limiting radiation exposure for vascular surgeons and staff – not to mention patients – during endovascular procedures involves a thorough understanding of dose metrics as well as risk factors for high-dose interventions, according to recent findings reported at a symposium on vascular surgery sponsored by Northwestern University.
Melissa Kirkwood, MD, of the University of Texas Southwestern Medical Center in Dallas, reported on her institution’s experience with limiting radiation exposure in typically high-dose cases. “What we found was that even though we had a substantial amount of dose in these cases – they included a significant proportion of 5- to 10-Gy and greater than 10-Gy cases – there were still no skin injuries detected in these patients,” she said, referencing retrospective and prospective analyses (J Vasc Surg. 2014;60:742-8; J Vasc Surg. 2015;61:902-6).
Vigilance regarding these principles for vascular surgeons is paramount, Dr. Kirkwood said, noting that the National Council on Radiation Protection and Measurements threshold for substantial radiation dose is 5 Gy or greater. “When you’re doing complex endovascular work, your doses can get that high,” she said.
As a means of measuring dose, Dr. Kirkwood called fluoroscopy time a “universally poor indicator” because in current practice vascular surgeons use digital acquisition mode in addition to fluoroscopy. “The digital acquisitions generate 10-100 times more dose than fluoroscopy, so if you’re only looking at fluoroscopy time, your potentially missing the majority of the dose for that case,” she said.
More applicable dose measures, she said, are kerma area product that measures total radiation beam output from the x-ray tube, which she called “a better reflection of operator exposure,” and reference air kerma (RAK), a measure of the dose at a reference point 15 cm along the beam axis toward the focal spot from the isocenter, which she said is the best approximation for patient peak skin dose exposure. However, the latter does not account for angle of the x-ray tube or patient position, which can vary based on the type of procedure or the patient’s size.
Dr. Kirkwood’s work at UTSW also determined that operator exposure during an endovascular procedure depends on where they stand. “Doubling the distance from the source can decrease the radiation level by a factor of four,” she said. For femoral access in the right groin, the operator is at greatest risk for exposure followed by the assistant when the assistant is standing to the right of the operator. The left brachial access site carries an even higher exposure for the operator, she said.
The table-mounted lead skirt plays a key role in limiting operator exposure, Dr. Kirkwood said. “It can be cumbersome, but it is very important in lowering your lower-body dose,” she said, because it will block radiation scatter coming off the bottom of the table.
At UTSW, the endovascular operators had a tutorial with the staff medical physicist on best practices to limit radiation exposure. “What we found was that we were significantly able to decrease the dose across all cases by simply going over a few principles,” she said.
Among those principles: “Always be aware when you’re on the fluoroscopy pedal and always use the lowest fluoroscopy mode possible,” she said. However, she noted that in difficult-to-visualize cases, a short-duration boost in fluoroscopy level might reduce overall fluoroscopy time and hence limit exposure. To limit digital acquisition mode, the use of fluoroscopic looping can allow for review of images during the procedure with a fraction of the dose that would be needed for a digital acquisition run.
Limiting magnification and using collimation can be complementary, Dr. Kirkwood said. “If you really have to magnify to see the area of interest, make sure you have tight collimation to try to decrease the scatter to you and your colleagues in the OR,” she said.
Dr. Kirkwood noted that raising the angio table as high as is comfortable and decreasing the distance between the source and image detector can limit patient exposure. Operators should avoid steep angulations of the x-ray tube, she said, but when angulations are necessary, operators should stand on the opposite side of the x-ray tube. “The best operating practice if you know you’re going to have a high-dose case with a lot of gantry angulation would be to tightly collimate to the area of interest and minimize the magnification,” she said.
Though not necessarily a principle, keeping up with software advances for imaging devices can also prove valuable for limiting radiation exposure, Dr. Kirkwood said. “It’s important to know about them because if you are purchasing new equipment, they are not necessarily included if you’re institution is looking to hold down costs,” she said.
Dr. Kirkwood had no relevant financial disclosures.
CHICAGO – Applying the key principles for limiting radiation exposure for vascular surgeons and staff – not to mention patients – during endovascular procedures involves a thorough understanding of dose metrics as well as risk factors for high-dose interventions, according to recent findings reported at a symposium on vascular surgery sponsored by Northwestern University.
Melissa Kirkwood, MD, of the University of Texas Southwestern Medical Center in Dallas, reported on her institution’s experience with limiting radiation exposure in typically high-dose cases. “What we found was that even though we had a substantial amount of dose in these cases – they included a significant proportion of 5- to 10-Gy and greater than 10-Gy cases – there were still no skin injuries detected in these patients,” she said, referencing retrospective and prospective analyses (J Vasc Surg. 2014;60:742-8; J Vasc Surg. 2015;61:902-6).
Vigilance regarding these principles for vascular surgeons is paramount, Dr. Kirkwood said, noting that the National Council on Radiation Protection and Measurements threshold for substantial radiation dose is 5 Gy or greater. “When you’re doing complex endovascular work, your doses can get that high,” she said.
As a means of measuring dose, Dr. Kirkwood called fluoroscopy time a “universally poor indicator” because in current practice vascular surgeons use digital acquisition mode in addition to fluoroscopy. “The digital acquisitions generate 10-100 times more dose than fluoroscopy, so if you’re only looking at fluoroscopy time, your potentially missing the majority of the dose for that case,” she said.
More applicable dose measures, she said, are kerma area product that measures total radiation beam output from the x-ray tube, which she called “a better reflection of operator exposure,” and reference air kerma (RAK), a measure of the dose at a reference point 15 cm along the beam axis toward the focal spot from the isocenter, which she said is the best approximation for patient peak skin dose exposure. However, the latter does not account for angle of the x-ray tube or patient position, which can vary based on the type of procedure or the patient’s size.
Dr. Kirkwood’s work at UTSW also determined that operator exposure during an endovascular procedure depends on where they stand. “Doubling the distance from the source can decrease the radiation level by a factor of four,” she said. For femoral access in the right groin, the operator is at greatest risk for exposure followed by the assistant when the assistant is standing to the right of the operator. The left brachial access site carries an even higher exposure for the operator, she said.
The table-mounted lead skirt plays a key role in limiting operator exposure, Dr. Kirkwood said. “It can be cumbersome, but it is very important in lowering your lower-body dose,” she said, because it will block radiation scatter coming off the bottom of the table.
At UTSW, the endovascular operators had a tutorial with the staff medical physicist on best practices to limit radiation exposure. “What we found was that we were significantly able to decrease the dose across all cases by simply going over a few principles,” she said.
Among those principles: “Always be aware when you’re on the fluoroscopy pedal and always use the lowest fluoroscopy mode possible,” she said. However, she noted that in difficult-to-visualize cases, a short-duration boost in fluoroscopy level might reduce overall fluoroscopy time and hence limit exposure. To limit digital acquisition mode, the use of fluoroscopic looping can allow for review of images during the procedure with a fraction of the dose that would be needed for a digital acquisition run.
Limiting magnification and using collimation can be complementary, Dr. Kirkwood said. “If you really have to magnify to see the area of interest, make sure you have tight collimation to try to decrease the scatter to you and your colleagues in the OR,” she said.
Dr. Kirkwood noted that raising the angio table as high as is comfortable and decreasing the distance between the source and image detector can limit patient exposure. Operators should avoid steep angulations of the x-ray tube, she said, but when angulations are necessary, operators should stand on the opposite side of the x-ray tube. “The best operating practice if you know you’re going to have a high-dose case with a lot of gantry angulation would be to tightly collimate to the area of interest and minimize the magnification,” she said.
Though not necessarily a principle, keeping up with software advances for imaging devices can also prove valuable for limiting radiation exposure, Dr. Kirkwood said. “It’s important to know about them because if you are purchasing new equipment, they are not necessarily included if you’re institution is looking to hold down costs,” she said.
Dr. Kirkwood had no relevant financial disclosures.
AT THE NORTHWESTERN VASCULAR SYMPOSIUM
Key clinical point: Vascular surgeons can lower their radiation exposure during endovascular procedures by employing key principles like appropriate shielding.
Major finding: Familiarity with dose terminology and metrics, possible radiation-induced injuries, and techniques to lower radiation dosing are keys to limiting radiation exposure.
Data source: Review of literature, including National Council on Radiation and Protection guidelines and National Cancer Institute grades of skin toxicity for radiation dermatitis.
Disclosures: Dr. Kirkwood had no financial relationships to disclose.
Two-thirds of patient advocacy groups receive industry funding
About two-thirds of patient advocacy organizations report receiving funds from for-profit firms, including pharmaceutical, device and biotechnology manufacturers, according to new survey results.
The study, published online Jan. 17 in JAMA Internal Medicine, sought responses from a randomly chosen sample of 439 executives at patient advocacy organizations (PAOs), of whom 66% (n = 289) responded. The median annual revenue for the groups surveyed was nearly $300,000, and 67% (n = 165) reported receiving at least some industry funding. Of those, 12% reported that more than half their annual funding comes from industry sources.
A total of 22 PAO leaders surveyed (8%) reported that they perceived pressure to conform their organizational interests to those of corporate donors (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.8443).
The vast majority of respondents (82%) said they found conflicts of interest to be relevant to PAOs, and most reported having a written policy on conflicts. More than half said they viewed their own organizations’ conflict of interest policies as sound.
The findings warrant a broad re-examination of PAO conflict-of-interest policies and disclosures, and a detailed examination of the specific ways in which PAOs are influenced or pressured, wrote Susannah L. Rose, PhD, of the Cleveland Clinic, and her colleagues.
PAOs do not routinely and publicly disclose all their sources of funding on websites, tax returns, or annual reports, and there are media investigations into some groups “regarding their ties to industry and the integrity of their activities,” the investigators wrote.
Dr. Rose and her colleagues recommended that PAOs disclose detailed information about industry funding on their websites and on Open Payments, a government website. The researchers acknowledged that their study relied on self-reported data, and though it was designed to obscure the identity of respondents and their organizations, the possibility of response bias exists.
Harvard University’s Edmond J. Safra Center for Ethics funded the study. One coauthor, Steven Joffe, MD, MPH, disclosed past funding from Genzyme Sanofi. No other conflicts were reported.
Industry funding strengthens and extends the much-needed patient voice in health care, but at what cost? During the EpiPen scandal, the manufacturer-sponsored advocacy groups were largely silent about price gouging. Recently, a drug company–funded “patient advocacy” campaign called “Even the Score” helped win regulatory approval for the thrice rejected controversial female sex drug flibanserin.
Just as the industry funding of clinical trials has been associated with more favorable findings, patient groups also face risks of bias when accepting money from companies seeking to expand markets for their new tests and treatments.
This new work demonstrates an urgent need for patient advocacy organizations to explicitly focus much more on representing the interests of patients and citizens, rather than serving – inadvertently or otherwise – the interests of their industry sponsors. In the meantime, we need much greater transparency about industry funding, including prominently displayed disclosures of dollar amounts and proportions of total funding on group websites, as well as addition of patient advocacy groups to the Open Payments program established by the Sunshine Act, which would mean mandatory disclosure of funding by sponsors.
Ray Moynihan, PhD, and Lisa Bero, PhD, are at the University of Sydney, New South Wales, Australia. Their comments are adapted from an editorial. They reported having no relevant financial disclosures. (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.9179 ).
Industry funding strengthens and extends the much-needed patient voice in health care, but at what cost? During the EpiPen scandal, the manufacturer-sponsored advocacy groups were largely silent about price gouging. Recently, a drug company–funded “patient advocacy” campaign called “Even the Score” helped win regulatory approval for the thrice rejected controversial female sex drug flibanserin.
Just as the industry funding of clinical trials has been associated with more favorable findings, patient groups also face risks of bias when accepting money from companies seeking to expand markets for their new tests and treatments.
This new work demonstrates an urgent need for patient advocacy organizations to explicitly focus much more on representing the interests of patients and citizens, rather than serving – inadvertently or otherwise – the interests of their industry sponsors. In the meantime, we need much greater transparency about industry funding, including prominently displayed disclosures of dollar amounts and proportions of total funding on group websites, as well as addition of patient advocacy groups to the Open Payments program established by the Sunshine Act, which would mean mandatory disclosure of funding by sponsors.
Ray Moynihan, PhD, and Lisa Bero, PhD, are at the University of Sydney, New South Wales, Australia. Their comments are adapted from an editorial. They reported having no relevant financial disclosures. (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.9179 ).
Industry funding strengthens and extends the much-needed patient voice in health care, but at what cost? During the EpiPen scandal, the manufacturer-sponsored advocacy groups were largely silent about price gouging. Recently, a drug company–funded “patient advocacy” campaign called “Even the Score” helped win regulatory approval for the thrice rejected controversial female sex drug flibanserin.
Just as the industry funding of clinical trials has been associated with more favorable findings, patient groups also face risks of bias when accepting money from companies seeking to expand markets for their new tests and treatments.
This new work demonstrates an urgent need for patient advocacy organizations to explicitly focus much more on representing the interests of patients and citizens, rather than serving – inadvertently or otherwise – the interests of their industry sponsors. In the meantime, we need much greater transparency about industry funding, including prominently displayed disclosures of dollar amounts and proportions of total funding on group websites, as well as addition of patient advocacy groups to the Open Payments program established by the Sunshine Act, which would mean mandatory disclosure of funding by sponsors.
Ray Moynihan, PhD, and Lisa Bero, PhD, are at the University of Sydney, New South Wales, Australia. Their comments are adapted from an editorial. They reported having no relevant financial disclosures. (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.9179 ).
About two-thirds of patient advocacy organizations report receiving funds from for-profit firms, including pharmaceutical, device and biotechnology manufacturers, according to new survey results.
The study, published online Jan. 17 in JAMA Internal Medicine, sought responses from a randomly chosen sample of 439 executives at patient advocacy organizations (PAOs), of whom 66% (n = 289) responded. The median annual revenue for the groups surveyed was nearly $300,000, and 67% (n = 165) reported receiving at least some industry funding. Of those, 12% reported that more than half their annual funding comes from industry sources.
A total of 22 PAO leaders surveyed (8%) reported that they perceived pressure to conform their organizational interests to those of corporate donors (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.8443).
The vast majority of respondents (82%) said they found conflicts of interest to be relevant to PAOs, and most reported having a written policy on conflicts. More than half said they viewed their own organizations’ conflict of interest policies as sound.
The findings warrant a broad re-examination of PAO conflict-of-interest policies and disclosures, and a detailed examination of the specific ways in which PAOs are influenced or pressured, wrote Susannah L. Rose, PhD, of the Cleveland Clinic, and her colleagues.
PAOs do not routinely and publicly disclose all their sources of funding on websites, tax returns, or annual reports, and there are media investigations into some groups “regarding their ties to industry and the integrity of their activities,” the investigators wrote.
Dr. Rose and her colleagues recommended that PAOs disclose detailed information about industry funding on their websites and on Open Payments, a government website. The researchers acknowledged that their study relied on self-reported data, and though it was designed to obscure the identity of respondents and their organizations, the possibility of response bias exists.
Harvard University’s Edmond J. Safra Center for Ethics funded the study. One coauthor, Steven Joffe, MD, MPH, disclosed past funding from Genzyme Sanofi. No other conflicts were reported.
About two-thirds of patient advocacy organizations report receiving funds from for-profit firms, including pharmaceutical, device and biotechnology manufacturers, according to new survey results.
The study, published online Jan. 17 in JAMA Internal Medicine, sought responses from a randomly chosen sample of 439 executives at patient advocacy organizations (PAOs), of whom 66% (n = 289) responded. The median annual revenue for the groups surveyed was nearly $300,000, and 67% (n = 165) reported receiving at least some industry funding. Of those, 12% reported that more than half their annual funding comes from industry sources.
A total of 22 PAO leaders surveyed (8%) reported that they perceived pressure to conform their organizational interests to those of corporate donors (JAMA Intern Med. 2017 Jan 17. doi: 10.1001/jamainternmed.2016.8443).
The vast majority of respondents (82%) said they found conflicts of interest to be relevant to PAOs, and most reported having a written policy on conflicts. More than half said they viewed their own organizations’ conflict of interest policies as sound.
The findings warrant a broad re-examination of PAO conflict-of-interest policies and disclosures, and a detailed examination of the specific ways in which PAOs are influenced or pressured, wrote Susannah L. Rose, PhD, of the Cleveland Clinic, and her colleagues.
PAOs do not routinely and publicly disclose all their sources of funding on websites, tax returns, or annual reports, and there are media investigations into some groups “regarding their ties to industry and the integrity of their activities,” the investigators wrote.
Dr. Rose and her colleagues recommended that PAOs disclose detailed information about industry funding on their websites and on Open Payments, a government website. The researchers acknowledged that their study relied on self-reported data, and though it was designed to obscure the identity of respondents and their organizations, the possibility of response bias exists.
Harvard University’s Edmond J. Safra Center for Ethics funded the study. One coauthor, Steven Joffe, MD, MPH, disclosed past funding from Genzyme Sanofi. No other conflicts were reported.
FROM JAMA INTERNAL MEDICINE
Key clinical point:
Major finding: A total of 67% of PAOs receive industry support, with 12% reporting funds comprising more than half their yearly funding.
Data source: A survey study sent to executives of 439 PAOs chosen at random; the response rate was 66%.
Disclosures: An ethics center at Harvard University sponsored the study; one coauthor reported prior funding from Genzyme Sanofi.
SOFA score may be best to identify sepsis in the ICU
Among critically ill patients admitted to the ICU with a suspected infection, defining sepsis by an increase of 2 or more points in the Sequential Organ Failure Assessment score yielded greater prognostic accuracy for in-hospital mortality, compared with the quick SOFA and the systemic inflammatory response syndrome criteria, results from a large analysis showed.
“Accurate diagnostic criteria and consensus definitions have an important role in adult intensive care medicine, providing tools for research, benchmarking, performance monitoring, and accreditation,” researchers from The Australian and New Zealand Intensive Care Society Centre for Outcomes and Resource Evaluation reported in the Jan. 17, 2017 edition of JAMA. “Seymour and colleagues published data concerning the validity of a 2 or more–point change in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score as a means of identifying sepsis among patients who are critically ill with suspected infection, assuming a SOFA of 0 for patients not known to have preexisting organ dysfunction (JAMA. 2016; 315[8]:762-74). In addition, the concept of the quick SOFA (qSOFA) score was introduced as a possible predictive tool among encounters with suspected infection outside the intensive care unit (ICU). These data were drawn from North American cohorts and a single German cohort and have not been validated externally.”
The mean age of the patients was 63 years, 45% were women, and the most common diagnosis was bacterial pneumonia (18%). Nearly 19% of patients died in the hospital and 56% died or experienced an ICU length of stay of at least 3 days or more. The researchers found that the SOFA score increased by 2 or more points in 90% of patients, while 87% manifested 2 or more SIRS criteria, and 54% had a qSOFA score of 2 or more points. In addition, discrimination of in-hospital mortality was significantly higher using SOFA (area under the receiving operating characteristic curve [AUROC], 0.753), compared with both SIRS criteria (AUROC, 0.589) and qSOFA (0.607); the between-group difference reached a P value of less than .001. Similar results were seen for the composite outcome of in-hospital mortality or an ICU length of stay of 3 days or more, which was higher using SOFA (AUROC, 0.736), compared with both SIRS criteria (AUROC, 0.609) and qSOFA (0.606); the between-group difference also reached a P value of less than .001.
The researchers acknowledged certain limitations of the study, including the fact that SOFA, SIRS criteria, and qSOFA could only be studied for the first 24 hours in the ICU. “Biochemical and physiological values could have come from any time within the first 24 hours of ICU admission and, as a result, could not be more accurately linked to the timing of the diagnosis of infection,” they wrote. “The SOFA score used should be considered a modification of the original because the cardiovascular component was estimated without knowledge of inotrope or vasopressor dose. The incidence of nosocomial infections and of infections in patients admitted with another diagnosis were unknown.”
Three of the seven study authors disclosed that they receive salary support from Monash University in Melbourne. The remainder reported having no financial disclosures.
It is neither surprising that qSOFA did not perform as well as the SOFA score in the ICU, given that this finding was already reported by Seymour et al. in their initial work, nor is it critically important because qSOFA is more likely to be useful outside of the ICU setting.
Thus, the findings ... support the results reported by Seymour et al. that qSOFA is potentially helpful in settings outside the ICU in rapidly identifying patients with suspected infection who have, or will likely develop, sepsis (JAMA. 2016;315[8]:762-74). However, qSOFA still warrants further testing, particularly in lower- and middle-income settings where context (for example, timing of presentation to the hospital among patients with a suspected infection) might vary considerably and such contextual factors might affect predictive validity. In addition, prospective studies may evaluate the utility of qSOFA when used longitudinally, with repeated measurements throughout the hospital stay. Arguably, the highest-quality evidence for validation of any tool to support clinical decision making would come from an analysis to establish whether decisions made with the support of the tool lead to better patient outcomes than those made by clinical judgment alone.
Ultimately, the utility of qSOFA will likely become surpassed if and when highly accurate, rapid diagnostic tests for sepsis emerge. For now, however, outside the ICU in the high-income settings where it has been tested, qSOFA appears a simple, rapid, inexpensive, and valid way to identify – among patients with suspected infection – those at a higher risk of having or developing sepsis.
Francois Lamontagne, MD, David A. Harrison, PhD, and Kathryn M. Rowan, PhD, are affiliated with the Intensive Care National Audit & Research Centre, London. Dr. Lamontagne reported serving as investigator for a study funded by GlaxoSmithKline and E-Motion. These comments are extracted from an editorial that appears in the Jan. 17, 2017 edition of JAMA (317[3]:267-8).
It is neither surprising that qSOFA did not perform as well as the SOFA score in the ICU, given that this finding was already reported by Seymour et al. in their initial work, nor is it critically important because qSOFA is more likely to be useful outside of the ICU setting.
Thus, the findings ... support the results reported by Seymour et al. that qSOFA is potentially helpful in settings outside the ICU in rapidly identifying patients with suspected infection who have, or will likely develop, sepsis (JAMA. 2016;315[8]:762-74). However, qSOFA still warrants further testing, particularly in lower- and middle-income settings where context (for example, timing of presentation to the hospital among patients with a suspected infection) might vary considerably and such contextual factors might affect predictive validity. In addition, prospective studies may evaluate the utility of qSOFA when used longitudinally, with repeated measurements throughout the hospital stay. Arguably, the highest-quality evidence for validation of any tool to support clinical decision making would come from an analysis to establish whether decisions made with the support of the tool lead to better patient outcomes than those made by clinical judgment alone.
Ultimately, the utility of qSOFA will likely become surpassed if and when highly accurate, rapid diagnostic tests for sepsis emerge. For now, however, outside the ICU in the high-income settings where it has been tested, qSOFA appears a simple, rapid, inexpensive, and valid way to identify – among patients with suspected infection – those at a higher risk of having or developing sepsis.
Francois Lamontagne, MD, David A. Harrison, PhD, and Kathryn M. Rowan, PhD, are affiliated with the Intensive Care National Audit & Research Centre, London. Dr. Lamontagne reported serving as investigator for a study funded by GlaxoSmithKline and E-Motion. These comments are extracted from an editorial that appears in the Jan. 17, 2017 edition of JAMA (317[3]:267-8).
It is neither surprising that qSOFA did not perform as well as the SOFA score in the ICU, given that this finding was already reported by Seymour et al. in their initial work, nor is it critically important because qSOFA is more likely to be useful outside of the ICU setting.
Thus, the findings ... support the results reported by Seymour et al. that qSOFA is potentially helpful in settings outside the ICU in rapidly identifying patients with suspected infection who have, or will likely develop, sepsis (JAMA. 2016;315[8]:762-74). However, qSOFA still warrants further testing, particularly in lower- and middle-income settings where context (for example, timing of presentation to the hospital among patients with a suspected infection) might vary considerably and such contextual factors might affect predictive validity. In addition, prospective studies may evaluate the utility of qSOFA when used longitudinally, with repeated measurements throughout the hospital stay. Arguably, the highest-quality evidence for validation of any tool to support clinical decision making would come from an analysis to establish whether decisions made with the support of the tool lead to better patient outcomes than those made by clinical judgment alone.
Ultimately, the utility of qSOFA will likely become surpassed if and when highly accurate, rapid diagnostic tests for sepsis emerge. For now, however, outside the ICU in the high-income settings where it has been tested, qSOFA appears a simple, rapid, inexpensive, and valid way to identify – among patients with suspected infection – those at a higher risk of having or developing sepsis.
Francois Lamontagne, MD, David A. Harrison, PhD, and Kathryn M. Rowan, PhD, are affiliated with the Intensive Care National Audit & Research Centre, London. Dr. Lamontagne reported serving as investigator for a study funded by GlaxoSmithKline and E-Motion. These comments are extracted from an editorial that appears in the Jan. 17, 2017 edition of JAMA (317[3]:267-8).
Among critically ill patients admitted to the ICU with a suspected infection, defining sepsis by an increase of 2 or more points in the Sequential Organ Failure Assessment score yielded greater prognostic accuracy for in-hospital mortality, compared with the quick SOFA and the systemic inflammatory response syndrome criteria, results from a large analysis showed.
“Accurate diagnostic criteria and consensus definitions have an important role in adult intensive care medicine, providing tools for research, benchmarking, performance monitoring, and accreditation,” researchers from The Australian and New Zealand Intensive Care Society Centre for Outcomes and Resource Evaluation reported in the Jan. 17, 2017 edition of JAMA. “Seymour and colleagues published data concerning the validity of a 2 or more–point change in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score as a means of identifying sepsis among patients who are critically ill with suspected infection, assuming a SOFA of 0 for patients not known to have preexisting organ dysfunction (JAMA. 2016; 315[8]:762-74). In addition, the concept of the quick SOFA (qSOFA) score was introduced as a possible predictive tool among encounters with suspected infection outside the intensive care unit (ICU). These data were drawn from North American cohorts and a single German cohort and have not been validated externally.”
The mean age of the patients was 63 years, 45% were women, and the most common diagnosis was bacterial pneumonia (18%). Nearly 19% of patients died in the hospital and 56% died or experienced an ICU length of stay of at least 3 days or more. The researchers found that the SOFA score increased by 2 or more points in 90% of patients, while 87% manifested 2 or more SIRS criteria, and 54% had a qSOFA score of 2 or more points. In addition, discrimination of in-hospital mortality was significantly higher using SOFA (area under the receiving operating characteristic curve [AUROC], 0.753), compared with both SIRS criteria (AUROC, 0.589) and qSOFA (0.607); the between-group difference reached a P value of less than .001. Similar results were seen for the composite outcome of in-hospital mortality or an ICU length of stay of 3 days or more, which was higher using SOFA (AUROC, 0.736), compared with both SIRS criteria (AUROC, 0.609) and qSOFA (0.606); the between-group difference also reached a P value of less than .001.
The researchers acknowledged certain limitations of the study, including the fact that SOFA, SIRS criteria, and qSOFA could only be studied for the first 24 hours in the ICU. “Biochemical and physiological values could have come from any time within the first 24 hours of ICU admission and, as a result, could not be more accurately linked to the timing of the diagnosis of infection,” they wrote. “The SOFA score used should be considered a modification of the original because the cardiovascular component was estimated without knowledge of inotrope or vasopressor dose. The incidence of nosocomial infections and of infections in patients admitted with another diagnosis were unknown.”
Three of the seven study authors disclosed that they receive salary support from Monash University in Melbourne. The remainder reported having no financial disclosures.
Among critically ill patients admitted to the ICU with a suspected infection, defining sepsis by an increase of 2 or more points in the Sequential Organ Failure Assessment score yielded greater prognostic accuracy for in-hospital mortality, compared with the quick SOFA and the systemic inflammatory response syndrome criteria, results from a large analysis showed.
“Accurate diagnostic criteria and consensus definitions have an important role in adult intensive care medicine, providing tools for research, benchmarking, performance monitoring, and accreditation,” researchers from The Australian and New Zealand Intensive Care Society Centre for Outcomes and Resource Evaluation reported in the Jan. 17, 2017 edition of JAMA. “Seymour and colleagues published data concerning the validity of a 2 or more–point change in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score as a means of identifying sepsis among patients who are critically ill with suspected infection, assuming a SOFA of 0 for patients not known to have preexisting organ dysfunction (JAMA. 2016; 315[8]:762-74). In addition, the concept of the quick SOFA (qSOFA) score was introduced as a possible predictive tool among encounters with suspected infection outside the intensive care unit (ICU). These data were drawn from North American cohorts and a single German cohort and have not been validated externally.”
The mean age of the patients was 63 years, 45% were women, and the most common diagnosis was bacterial pneumonia (18%). Nearly 19% of patients died in the hospital and 56% died or experienced an ICU length of stay of at least 3 days or more. The researchers found that the SOFA score increased by 2 or more points in 90% of patients, while 87% manifested 2 or more SIRS criteria, and 54% had a qSOFA score of 2 or more points. In addition, discrimination of in-hospital mortality was significantly higher using SOFA (area under the receiving operating characteristic curve [AUROC], 0.753), compared with both SIRS criteria (AUROC, 0.589) and qSOFA (0.607); the between-group difference reached a P value of less than .001. Similar results were seen for the composite outcome of in-hospital mortality or an ICU length of stay of 3 days or more, which was higher using SOFA (AUROC, 0.736), compared with both SIRS criteria (AUROC, 0.609) and qSOFA (0.606); the between-group difference also reached a P value of less than .001.
The researchers acknowledged certain limitations of the study, including the fact that SOFA, SIRS criteria, and qSOFA could only be studied for the first 24 hours in the ICU. “Biochemical and physiological values could have come from any time within the first 24 hours of ICU admission and, as a result, could not be more accurately linked to the timing of the diagnosis of infection,” they wrote. “The SOFA score used should be considered a modification of the original because the cardiovascular component was estimated without knowledge of inotrope or vasopressor dose. The incidence of nosocomial infections and of infections in patients admitted with another diagnosis were unknown.”
Three of the seven study authors disclosed that they receive salary support from Monash University in Melbourne. The remainder reported having no financial disclosures.
FROM JAMA
Key clinical point:
Major finding: The SOFA score increased by 2 or more points in 90% of patients, while 87% manifested 2 or more SIRS criteria, and 54% had a qSOFA score of 2 or more points.
Data source: A retrospective cohort study of 184,875 patients with an infection-related primary diagnosis who were admitted to 182 ICUs in Australia and New Zealand between 2000 and 2015.
Disclosures: Three of the seven study authors disclosed that they receive salary support from Monash University in Melbourne. The remainder reported having no financial disclosures.
Telmisartan-Induced Lichen Planus Eruption Manifested on Vitiliginous Skin
To the Editor:
A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.
Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.
A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).
On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.
The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.
The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).
Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.
The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.6 Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.7 Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.8,9
Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.10
Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.
Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.
Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.
Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.11 In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.12 Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.13
Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.
Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8+ T cells to CD4+ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8+ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.
Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.
Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).
- Pilli M, Zerbini A, Vescovi P, et al. Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response. Hepatology. 2002;36:1446-1452.
- De Vries HJ, van Marle J, Teunissen MB, et al. Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells. Br J Dermatol. 2006;154:361-364.
- De Vries HJ, Teunissen MB, Zorgdrager F, et al. Lichen planus remission is associated with a decrease of human herpes virus type 7 protein expression in plasmacytoid dendritic cells. Arch Dermatol Res. 2007;299:213-219.
- Requena L, Kutzner H, Escalonilla P, et al. Cutaneous reactions at sites of herpes zoster scars: an expanded spectrum. Br J Dermatol. 1998;138:161-168.
- Al-Khenaizan S. Lichen planus occurring after hepatitis B vaccination: a new case. J Am Acad Dermatol. 2001;45:614-615.
- Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25:593-619.
- Sadr-Ashkevari S. Familial actinic lichen planus: case reports in two brothers. Arch Int Med. 2001;4:204-206.
- Manolache L, Seceleanu-Petrescu D, Benea V. Lichen planus patients and stressful events. J Eur Acad Dermatol Venereol. 2008;22:437-441.
- Mahood JM. Familial lichen planus. Arch Dermatol. 1983;119:292-294.
- Shimizu M, Higaki Y, Higaki M, et al. The role of granzyme B-expressing CD8-positive T cells in apoptosis of keratinocytes in lichen planus. Arch Dermatol Res. 1997;289:527-532.
- Bécherel PA, Bussel A, Chosidow O, et al. Extracorporeal photochemotherapy for chronic erosive lichen planus. Lancet. 1998;351:805.
- Trehan M, Taylar CR. Low-dose excimer 308-nm laser for the treatment of oral lichen planus. Arch Dermatol. 2004;140:415-420.
- Wackernagel A, Legat FJ, Hofer A, et al. Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus. Photodermatol Photoimmunol Photomed. 2007;23:15-19.
- Fellner MJ. Lichen planus. Int J Dermatol. 1980;19:71-75.
- Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf. 2002;25:345-372.
- Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90-100.
To the Editor:
A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.
Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.
A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).
On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.
The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.
The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).
Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.
The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.6 Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.7 Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.8,9
Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.10
Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.
Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.
Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.
Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.11 In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.12 Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.13
Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.
Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8+ T cells to CD4+ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8+ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.
Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.
Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).
To the Editor:
A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.
Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.
A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).
On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.
The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.
The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).
Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.
The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.6 Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.7 Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.8,9
Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.10
Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.
Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.
Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.
Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.11 In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.12 Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.13
Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.
Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8+ T cells to CD4+ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8+ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.
Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.
Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).
- Pilli M, Zerbini A, Vescovi P, et al. Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response. Hepatology. 2002;36:1446-1452.
- De Vries HJ, van Marle J, Teunissen MB, et al. Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells. Br J Dermatol. 2006;154:361-364.
- De Vries HJ, Teunissen MB, Zorgdrager F, et al. Lichen planus remission is associated with a decrease of human herpes virus type 7 protein expression in plasmacytoid dendritic cells. Arch Dermatol Res. 2007;299:213-219.
- Requena L, Kutzner H, Escalonilla P, et al. Cutaneous reactions at sites of herpes zoster scars: an expanded spectrum. Br J Dermatol. 1998;138:161-168.
- Al-Khenaizan S. Lichen planus occurring after hepatitis B vaccination: a new case. J Am Acad Dermatol. 2001;45:614-615.
- Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25:593-619.
- Sadr-Ashkevari S. Familial actinic lichen planus: case reports in two brothers. Arch Int Med. 2001;4:204-206.
- Manolache L, Seceleanu-Petrescu D, Benea V. Lichen planus patients and stressful events. J Eur Acad Dermatol Venereol. 2008;22:437-441.
- Mahood JM. Familial lichen planus. Arch Dermatol. 1983;119:292-294.
- Shimizu M, Higaki Y, Higaki M, et al. The role of granzyme B-expressing CD8-positive T cells in apoptosis of keratinocytes in lichen planus. Arch Dermatol Res. 1997;289:527-532.
- Bécherel PA, Bussel A, Chosidow O, et al. Extracorporeal photochemotherapy for chronic erosive lichen planus. Lancet. 1998;351:805.
- Trehan M, Taylar CR. Low-dose excimer 308-nm laser for the treatment of oral lichen planus. Arch Dermatol. 2004;140:415-420.
- Wackernagel A, Legat FJ, Hofer A, et al. Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus. Photodermatol Photoimmunol Photomed. 2007;23:15-19.
- Fellner MJ. Lichen planus. Int J Dermatol. 1980;19:71-75.
- Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf. 2002;25:345-372.
- Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90-100.
- Pilli M, Zerbini A, Vescovi P, et al. Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response. Hepatology. 2002;36:1446-1452.
- De Vries HJ, van Marle J, Teunissen MB, et al. Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells. Br J Dermatol. 2006;154:361-364.
- De Vries HJ, Teunissen MB, Zorgdrager F, et al. Lichen planus remission is associated with a decrease of human herpes virus type 7 protein expression in plasmacytoid dendritic cells. Arch Dermatol Res. 2007;299:213-219.
- Requena L, Kutzner H, Escalonilla P, et al. Cutaneous reactions at sites of herpes zoster scars: an expanded spectrum. Br J Dermatol. 1998;138:161-168.
- Al-Khenaizan S. Lichen planus occurring after hepatitis B vaccination: a new case. J Am Acad Dermatol. 2001;45:614-615.
- Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25:593-619.
- Sadr-Ashkevari S. Familial actinic lichen planus: case reports in two brothers. Arch Int Med. 2001;4:204-206.
- Manolache L, Seceleanu-Petrescu D, Benea V. Lichen planus patients and stressful events. J Eur Acad Dermatol Venereol. 2008;22:437-441.
- Mahood JM. Familial lichen planus. Arch Dermatol. 1983;119:292-294.
- Shimizu M, Higaki Y, Higaki M, et al. The role of granzyme B-expressing CD8-positive T cells in apoptosis of keratinocytes in lichen planus. Arch Dermatol Res. 1997;289:527-532.
- Bécherel PA, Bussel A, Chosidow O, et al. Extracorporeal photochemotherapy for chronic erosive lichen planus. Lancet. 1998;351:805.
- Trehan M, Taylar CR. Low-dose excimer 308-nm laser for the treatment of oral lichen planus. Arch Dermatol. 2004;140:415-420.
- Wackernagel A, Legat FJ, Hofer A, et al. Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus. Photodermatol Photoimmunol Photomed. 2007;23:15-19.
- Fellner MJ. Lichen planus. Int J Dermatol. 1980;19:71-75.
- Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf. 2002;25:345-372.
- Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90-100.
Practice Points
- Lichen planus (LP) is a T-cell–mediated autoimmune disease that affects the skin and often the mucosa, nails, and scalp.
- The etiology of LP is unknown. It can be induced by a variety of medications and may spread through the isomorphic phenomenon.
- Immune factors play a role in the development of LP, drug-induced LP, and vitiligo.
Bilateral Symmetric Onycholysis of Distal Fingernails
The Diagnosis: Allergic Contact Dermatitis
An allergic contact dermatitis (ACD) to acrylates was suspected and 4 patches were applied to the forearm (the North American Standard Series of the North American Contact Dermatitis Group). The patches were 2-hydroxyethyl methacrylate (2-HEMA) 2.0% permissible exposure limit (peL), ethyl acrylate 0.1% peL, tosylamide formaldehyde resin 10.0% peL, and methyl methacrylate 2.0% peL. A reading at 72 hours was performed and showed a positive reaction to hydroxyethyl methacrylate, ethyl acrylate, and methyl methacrylate, and a negative patch test to tosylamide formaldehyde resin (nail polish)(Figure). The patient was diagnosed with an allergic contact hypersensitivity to the aforementioned acrylates and instructed to avoid artificial nails and acrylate glues. She also was started on oral biotin supplements. On 6-month follow-up the patient had regrowth of all 10 fingernails without brittleness or splitting. She was able to use nail polishes but avoided all acrylic artificial nails and acrylate-containing personal care products.
Acrylate Allergy and Artificial Nails
Acrylates are plastic materials formed by polymerization of acrylic or methacrylic acid monomers and have been cited as a major cause of occupational and nonoccupational contact dermatitis. Contact dermatitis to acrylates in artificial nails was first reported in the 1950s.1,2 Products containing 100% methyl methacrylate monomers in acrylic nails were banned by the US Food and Drug Administration in the early 1970s after receiving a number of complaints.3 However, no regulation prohibits the use of methyl methacrylate monomer in cosmetic products, and various methacrylate and acrylate monomers remain widely used.4 With a growing popularity in artificial nails, it is expected the number of sensitized persons will increase.
Acrylate allergy from sculptured nails concern self-curing resins made from a polymer powder and a liquid monomer solution. Advantages of new UV-cured products include the lack of unpleasant smell and simplified modeling. They also do not require an irritant, such as methacrylic acid, as a bonding agent. Instead, 2-HEMA and 2-hydroxypropyl methacrylate are added. These photobonded nails colloquially are called gel nails (acid free) as opposed to acrylic nails (using methacrylic acid as a primer). It is important to note that the esters of acrylic acid but not the acid itself sensitize patients, and sensitization is not caused by the uncured gel or the monomer solution but by the remaining monomers in the cured plastic nail and the dust filings that are produced during the finishing process.
Clinical Presentation
Symptoms of an ACD to nail acrylates include pruritus and fingertip dermatitis along with nail plate dystrophy. There may be pruritus at the nail base, with subsequent dryness, thickening, and onycholysis. The brittle nails may become split, discolored, and develop paronychia. Inadvertent contact with glue monomers or other acrylate-containing substances may cause eczematous lesions at distant sites. Avoidance of the allergen often results in complete restoration of the normal nail and fingertip within months.
Sensitization
Acrylates and methacrylates are ubiquitous materials used for both industrial and commercial applications. Due to their widespread industrial use, contact allergies to acrylates including 2-HEMA, 2-hydroxypropyl methacrylate, and triethyleneglycol diacrylate (TREGDA) are common. Cross-reaction of these compounds has been observed and is postulated to be due to reaction of the (meth)acrylate carboxyethyl group with the receptors of antigen-presenting cells.5 As a result, an individual with an acrylate allergy sensitized to one allergen often is allergic to its similar compounds and cross-reactors and must avoid the assortment of compounds containing these ingredients, which is important for individuals with occupational sensitization to a particular acrylate who is subsequently susceptible to other acrylate-containing compounds triggering allergic reactions when reexposure occurs in different settings.
Allergens and Occupational Exposure
Acrylates in cosmetic nail products are a source of ACD for not only the customer but also the manicurist.6 The most frequently cited sources of ACD in beauticians are acrylate chemicals.7 However, acrylate compounds are an occupational hazard for a number of other specialists, including dentists and dental technicians, histology technicians, and individuals in the printing industry.8,9 Other individuals may be sensitized to acrylates through their inclusion in adhesives, dental bonding agents, hearing aids, electrocardiogram electrodes, artificial bone cement, and a myriad of other medical and nonmedical applications.4,10-12 For workers who cannot avoid occupational exposure to these allergens, polyvinyl alcohol and multilayer laminate gloves are recommended, as natural rubber latex gloves do not always provide adequate protection from many of these agents.10
Testing for Suspected Acrylate Allergy
Cross-reactivity among acrylates is widely considered in the literature but remains enigmatic and is an important consideration with regard to routine patch test screening.13 In the case of an acrylate allergy to nail products, using 2-HEMA and ethylene glycol dimethacrylate is effective in detecting sensitization by photobonded nails and in patients sensitized by powder liquid products.14 One study showed a patch test panel including 2-HEMA, ethylene glycol dimethacrylate, and TREGDA was effective in identifying the majority of individuals with an allergy to acrylates in nail products and nail technicians.15 Another study has shown the most commonly positive testing allergens to be HEMA, ethyl acrylate, and methyl methacrylate.16 If one is patch testing only one chemical, it appears 2-HEMA is preferred.17 However, broader panels of screening allergens are necessary to achieve an accurate diagnosis. Furthermore, different panels of test allergens have been shown to vary in their ability to detect an acrylate allergy in different occupational exposures.12
The time to patch test read also is important. A standard read at 72 hours is warranted; however, one study showed if only one read at day 3 was done without a subsequent day 7 read, then 25% of TREGDA and 50% of 2-HEMA allergies would have been missed in patients with occupational acrylate allergy.15 Other studies have reported late-appearing and long-lasting test reactions when testing for an acrylate allergy.18,19 Clinicians should be cognizant that an acrylate allergy may be present even if initial screening is negative but the history and clinical picture are suggestive.
- Canizares O. Contact dermatitis due to the acrylic materials used in artificial nails. AMA Arch Derm. 1956;74:141-143.
- Fisher AA, Franks A, Glick H. Allergic sensitization of the skin and nails to acrylic plastic nails. J Allergy. 1957;28:84-88.
- US Food and Drug Administration. Nail care products. http://www.fda.gov/Cosmetics/ProductsIngredients/Products/ucm127068.htm. Updated October 26, 2016. Accessed December 27, 2016.
- Haughton AM, Belsito DV. Acrylate allergy induced by acrylic nails resulting in prosthesis failure. J Am Acad Dermatol. 2008;59(5 suppl):S123-S124.
- Kanerva L. Cross-reactions of multifunctional methacrylates and acrylates. Acta Odontol Scand. 2001;59:320-329.
- Tammaro A, Narcisi A, Abruzzese C, et al. Fingertip dermatitis: occupational acrylate cross reaction. Allergol Int. 2014;63:609-610.
- Kwok C, Money A, Carder M, et al. Cases of occupational dermatitis and asthma in beauticians that were reported to The Health and Occupation Research (THOR) network from 1996 to 2011. Clin Exp Dermatol. 2014;39:590-595.
- Aalto-Korte K, Alanko K, Kuuliala O, et al. Methacrylate and acrylate allergy in dental personnel. Contact Dermatitis. 2007;57:324-330.
- Molina L, Amado A, Mattei PL 4th, et al. Contact dermatitis from acrylics in a histology laboratory assistant. Dermatitis. 2009;20:E11-E12.
- Prasad Hunasehally RY, Hughes TM, Stone NM. Atypical pattern of (meth)acrylate allergic contact dermatitis in dental professionals. Br Dent J. 2012;213:223-224.
- Stingeni L, Cerulli E, Spalletti A, et al. The role of acrylic acid impurity as a sensitizing component in electrocardiogram electrodes [published online January 27, 2015]. Contact Dermatitis. 2015;73:44-48.
- Sasseville D. Acrylates in contact dermatitis. Dermatitis. 2012;23:6-16.
- Fisher AA. Cross reactions between methyl methacrylate monomer and acrylic monomers presently used in acrylic nail preparations. Contact Dermatitis. 1980;6:345-347.
- Hemmer W, Focke M, Wantke F, et al. Allergic contact dermatitis to artificial fingernails prepared from UV light-cured acrylates. J Am Acad Dermatol. 1996;35(3, pt 1):377-380.
- Teik-Jin Goon A, Bruze M, Zimerson E, et al. Contact allergy to acrylates/methacrylates in the acrylate and nail acrylics series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2007;57:21-27.
- Drucker AM, Pratt MD. Acrylate contact allergy: patient characteristics and evaluation of screening allergens. Dermatitis. 2011;22:98-101.
- Ramos L, Cabral R, Goncalo M. Allergic contact dermatitis caused by acrylates and methacrylates--a 7-year study. Contact Dermatitis. 2014;71:102-107.
- Goon AT, Isaksson M, Zimerson E, et al. Contact allergy to (meth)acrylates in the dental series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2006;55:219-226.
- Isaksson M, Lindberg M, Sundberg K, et al. The development and course of patch-test reactions to 2-hydroxyethyl methacrylate and ethyleneglycol dimethacrylate. Contact Dermatitis. 2005;53:292-297.
The Diagnosis: Allergic Contact Dermatitis
An allergic contact dermatitis (ACD) to acrylates was suspected and 4 patches were applied to the forearm (the North American Standard Series of the North American Contact Dermatitis Group). The patches were 2-hydroxyethyl methacrylate (2-HEMA) 2.0% permissible exposure limit (peL), ethyl acrylate 0.1% peL, tosylamide formaldehyde resin 10.0% peL, and methyl methacrylate 2.0% peL. A reading at 72 hours was performed and showed a positive reaction to hydroxyethyl methacrylate, ethyl acrylate, and methyl methacrylate, and a negative patch test to tosylamide formaldehyde resin (nail polish)(Figure). The patient was diagnosed with an allergic contact hypersensitivity to the aforementioned acrylates and instructed to avoid artificial nails and acrylate glues. She also was started on oral biotin supplements. On 6-month follow-up the patient had regrowth of all 10 fingernails without brittleness or splitting. She was able to use nail polishes but avoided all acrylic artificial nails and acrylate-containing personal care products.
Acrylate Allergy and Artificial Nails
Acrylates are plastic materials formed by polymerization of acrylic or methacrylic acid monomers and have been cited as a major cause of occupational and nonoccupational contact dermatitis. Contact dermatitis to acrylates in artificial nails was first reported in the 1950s.1,2 Products containing 100% methyl methacrylate monomers in acrylic nails were banned by the US Food and Drug Administration in the early 1970s after receiving a number of complaints.3 However, no regulation prohibits the use of methyl methacrylate monomer in cosmetic products, and various methacrylate and acrylate monomers remain widely used.4 With a growing popularity in artificial nails, it is expected the number of sensitized persons will increase.
Acrylate allergy from sculptured nails concern self-curing resins made from a polymer powder and a liquid monomer solution. Advantages of new UV-cured products include the lack of unpleasant smell and simplified modeling. They also do not require an irritant, such as methacrylic acid, as a bonding agent. Instead, 2-HEMA and 2-hydroxypropyl methacrylate are added. These photobonded nails colloquially are called gel nails (acid free) as opposed to acrylic nails (using methacrylic acid as a primer). It is important to note that the esters of acrylic acid but not the acid itself sensitize patients, and sensitization is not caused by the uncured gel or the monomer solution but by the remaining monomers in the cured plastic nail and the dust filings that are produced during the finishing process.
Clinical Presentation
Symptoms of an ACD to nail acrylates include pruritus and fingertip dermatitis along with nail plate dystrophy. There may be pruritus at the nail base, with subsequent dryness, thickening, and onycholysis. The brittle nails may become split, discolored, and develop paronychia. Inadvertent contact with glue monomers or other acrylate-containing substances may cause eczematous lesions at distant sites. Avoidance of the allergen often results in complete restoration of the normal nail and fingertip within months.
Sensitization
Acrylates and methacrylates are ubiquitous materials used for both industrial and commercial applications. Due to their widespread industrial use, contact allergies to acrylates including 2-HEMA, 2-hydroxypropyl methacrylate, and triethyleneglycol diacrylate (TREGDA) are common. Cross-reaction of these compounds has been observed and is postulated to be due to reaction of the (meth)acrylate carboxyethyl group with the receptors of antigen-presenting cells.5 As a result, an individual with an acrylate allergy sensitized to one allergen often is allergic to its similar compounds and cross-reactors and must avoid the assortment of compounds containing these ingredients, which is important for individuals with occupational sensitization to a particular acrylate who is subsequently susceptible to other acrylate-containing compounds triggering allergic reactions when reexposure occurs in different settings.
Allergens and Occupational Exposure
Acrylates in cosmetic nail products are a source of ACD for not only the customer but also the manicurist.6 The most frequently cited sources of ACD in beauticians are acrylate chemicals.7 However, acrylate compounds are an occupational hazard for a number of other specialists, including dentists and dental technicians, histology technicians, and individuals in the printing industry.8,9 Other individuals may be sensitized to acrylates through their inclusion in adhesives, dental bonding agents, hearing aids, electrocardiogram electrodes, artificial bone cement, and a myriad of other medical and nonmedical applications.4,10-12 For workers who cannot avoid occupational exposure to these allergens, polyvinyl alcohol and multilayer laminate gloves are recommended, as natural rubber latex gloves do not always provide adequate protection from many of these agents.10
Testing for Suspected Acrylate Allergy
Cross-reactivity among acrylates is widely considered in the literature but remains enigmatic and is an important consideration with regard to routine patch test screening.13 In the case of an acrylate allergy to nail products, using 2-HEMA and ethylene glycol dimethacrylate is effective in detecting sensitization by photobonded nails and in patients sensitized by powder liquid products.14 One study showed a patch test panel including 2-HEMA, ethylene glycol dimethacrylate, and TREGDA was effective in identifying the majority of individuals with an allergy to acrylates in nail products and nail technicians.15 Another study has shown the most commonly positive testing allergens to be HEMA, ethyl acrylate, and methyl methacrylate.16 If one is patch testing only one chemical, it appears 2-HEMA is preferred.17 However, broader panels of screening allergens are necessary to achieve an accurate diagnosis. Furthermore, different panels of test allergens have been shown to vary in their ability to detect an acrylate allergy in different occupational exposures.12
The time to patch test read also is important. A standard read at 72 hours is warranted; however, one study showed if only one read at day 3 was done without a subsequent day 7 read, then 25% of TREGDA and 50% of 2-HEMA allergies would have been missed in patients with occupational acrylate allergy.15 Other studies have reported late-appearing and long-lasting test reactions when testing for an acrylate allergy.18,19 Clinicians should be cognizant that an acrylate allergy may be present even if initial screening is negative but the history and clinical picture are suggestive.
The Diagnosis: Allergic Contact Dermatitis
An allergic contact dermatitis (ACD) to acrylates was suspected and 4 patches were applied to the forearm (the North American Standard Series of the North American Contact Dermatitis Group). The patches were 2-hydroxyethyl methacrylate (2-HEMA) 2.0% permissible exposure limit (peL), ethyl acrylate 0.1% peL, tosylamide formaldehyde resin 10.0% peL, and methyl methacrylate 2.0% peL. A reading at 72 hours was performed and showed a positive reaction to hydroxyethyl methacrylate, ethyl acrylate, and methyl methacrylate, and a negative patch test to tosylamide formaldehyde resin (nail polish)(Figure). The patient was diagnosed with an allergic contact hypersensitivity to the aforementioned acrylates and instructed to avoid artificial nails and acrylate glues. She also was started on oral biotin supplements. On 6-month follow-up the patient had regrowth of all 10 fingernails without brittleness or splitting. She was able to use nail polishes but avoided all acrylic artificial nails and acrylate-containing personal care products.
Acrylate Allergy and Artificial Nails
Acrylates are plastic materials formed by polymerization of acrylic or methacrylic acid monomers and have been cited as a major cause of occupational and nonoccupational contact dermatitis. Contact dermatitis to acrylates in artificial nails was first reported in the 1950s.1,2 Products containing 100% methyl methacrylate monomers in acrylic nails were banned by the US Food and Drug Administration in the early 1970s after receiving a number of complaints.3 However, no regulation prohibits the use of methyl methacrylate monomer in cosmetic products, and various methacrylate and acrylate monomers remain widely used.4 With a growing popularity in artificial nails, it is expected the number of sensitized persons will increase.
Acrylate allergy from sculptured nails concern self-curing resins made from a polymer powder and a liquid monomer solution. Advantages of new UV-cured products include the lack of unpleasant smell and simplified modeling. They also do not require an irritant, such as methacrylic acid, as a bonding agent. Instead, 2-HEMA and 2-hydroxypropyl methacrylate are added. These photobonded nails colloquially are called gel nails (acid free) as opposed to acrylic nails (using methacrylic acid as a primer). It is important to note that the esters of acrylic acid but not the acid itself sensitize patients, and sensitization is not caused by the uncured gel or the monomer solution but by the remaining monomers in the cured plastic nail and the dust filings that are produced during the finishing process.
Clinical Presentation
Symptoms of an ACD to nail acrylates include pruritus and fingertip dermatitis along with nail plate dystrophy. There may be pruritus at the nail base, with subsequent dryness, thickening, and onycholysis. The brittle nails may become split, discolored, and develop paronychia. Inadvertent contact with glue monomers or other acrylate-containing substances may cause eczematous lesions at distant sites. Avoidance of the allergen often results in complete restoration of the normal nail and fingertip within months.
Sensitization
Acrylates and methacrylates are ubiquitous materials used for both industrial and commercial applications. Due to their widespread industrial use, contact allergies to acrylates including 2-HEMA, 2-hydroxypropyl methacrylate, and triethyleneglycol diacrylate (TREGDA) are common. Cross-reaction of these compounds has been observed and is postulated to be due to reaction of the (meth)acrylate carboxyethyl group with the receptors of antigen-presenting cells.5 As a result, an individual with an acrylate allergy sensitized to one allergen often is allergic to its similar compounds and cross-reactors and must avoid the assortment of compounds containing these ingredients, which is important for individuals with occupational sensitization to a particular acrylate who is subsequently susceptible to other acrylate-containing compounds triggering allergic reactions when reexposure occurs in different settings.
Allergens and Occupational Exposure
Acrylates in cosmetic nail products are a source of ACD for not only the customer but also the manicurist.6 The most frequently cited sources of ACD in beauticians are acrylate chemicals.7 However, acrylate compounds are an occupational hazard for a number of other specialists, including dentists and dental technicians, histology technicians, and individuals in the printing industry.8,9 Other individuals may be sensitized to acrylates through their inclusion in adhesives, dental bonding agents, hearing aids, electrocardiogram electrodes, artificial bone cement, and a myriad of other medical and nonmedical applications.4,10-12 For workers who cannot avoid occupational exposure to these allergens, polyvinyl alcohol and multilayer laminate gloves are recommended, as natural rubber latex gloves do not always provide adequate protection from many of these agents.10
Testing for Suspected Acrylate Allergy
Cross-reactivity among acrylates is widely considered in the literature but remains enigmatic and is an important consideration with regard to routine patch test screening.13 In the case of an acrylate allergy to nail products, using 2-HEMA and ethylene glycol dimethacrylate is effective in detecting sensitization by photobonded nails and in patients sensitized by powder liquid products.14 One study showed a patch test panel including 2-HEMA, ethylene glycol dimethacrylate, and TREGDA was effective in identifying the majority of individuals with an allergy to acrylates in nail products and nail technicians.15 Another study has shown the most commonly positive testing allergens to be HEMA, ethyl acrylate, and methyl methacrylate.16 If one is patch testing only one chemical, it appears 2-HEMA is preferred.17 However, broader panels of screening allergens are necessary to achieve an accurate diagnosis. Furthermore, different panels of test allergens have been shown to vary in their ability to detect an acrylate allergy in different occupational exposures.12
The time to patch test read also is important. A standard read at 72 hours is warranted; however, one study showed if only one read at day 3 was done without a subsequent day 7 read, then 25% of TREGDA and 50% of 2-HEMA allergies would have been missed in patients with occupational acrylate allergy.15 Other studies have reported late-appearing and long-lasting test reactions when testing for an acrylate allergy.18,19 Clinicians should be cognizant that an acrylate allergy may be present even if initial screening is negative but the history and clinical picture are suggestive.
- Canizares O. Contact dermatitis due to the acrylic materials used in artificial nails. AMA Arch Derm. 1956;74:141-143.
- Fisher AA, Franks A, Glick H. Allergic sensitization of the skin and nails to acrylic plastic nails. J Allergy. 1957;28:84-88.
- US Food and Drug Administration. Nail care products. http://www.fda.gov/Cosmetics/ProductsIngredients/Products/ucm127068.htm. Updated October 26, 2016. Accessed December 27, 2016.
- Haughton AM, Belsito DV. Acrylate allergy induced by acrylic nails resulting in prosthesis failure. J Am Acad Dermatol. 2008;59(5 suppl):S123-S124.
- Kanerva L. Cross-reactions of multifunctional methacrylates and acrylates. Acta Odontol Scand. 2001;59:320-329.
- Tammaro A, Narcisi A, Abruzzese C, et al. Fingertip dermatitis: occupational acrylate cross reaction. Allergol Int. 2014;63:609-610.
- Kwok C, Money A, Carder M, et al. Cases of occupational dermatitis and asthma in beauticians that were reported to The Health and Occupation Research (THOR) network from 1996 to 2011. Clin Exp Dermatol. 2014;39:590-595.
- Aalto-Korte K, Alanko K, Kuuliala O, et al. Methacrylate and acrylate allergy in dental personnel. Contact Dermatitis. 2007;57:324-330.
- Molina L, Amado A, Mattei PL 4th, et al. Contact dermatitis from acrylics in a histology laboratory assistant. Dermatitis. 2009;20:E11-E12.
- Prasad Hunasehally RY, Hughes TM, Stone NM. Atypical pattern of (meth)acrylate allergic contact dermatitis in dental professionals. Br Dent J. 2012;213:223-224.
- Stingeni L, Cerulli E, Spalletti A, et al. The role of acrylic acid impurity as a sensitizing component in electrocardiogram electrodes [published online January 27, 2015]. Contact Dermatitis. 2015;73:44-48.
- Sasseville D. Acrylates in contact dermatitis. Dermatitis. 2012;23:6-16.
- Fisher AA. Cross reactions between methyl methacrylate monomer and acrylic monomers presently used in acrylic nail preparations. Contact Dermatitis. 1980;6:345-347.
- Hemmer W, Focke M, Wantke F, et al. Allergic contact dermatitis to artificial fingernails prepared from UV light-cured acrylates. J Am Acad Dermatol. 1996;35(3, pt 1):377-380.
- Teik-Jin Goon A, Bruze M, Zimerson E, et al. Contact allergy to acrylates/methacrylates in the acrylate and nail acrylics series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2007;57:21-27.
- Drucker AM, Pratt MD. Acrylate contact allergy: patient characteristics and evaluation of screening allergens. Dermatitis. 2011;22:98-101.
- Ramos L, Cabral R, Goncalo M. Allergic contact dermatitis caused by acrylates and methacrylates--a 7-year study. Contact Dermatitis. 2014;71:102-107.
- Goon AT, Isaksson M, Zimerson E, et al. Contact allergy to (meth)acrylates in the dental series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2006;55:219-226.
- Isaksson M, Lindberg M, Sundberg K, et al. The development and course of patch-test reactions to 2-hydroxyethyl methacrylate and ethyleneglycol dimethacrylate. Contact Dermatitis. 2005;53:292-297.
- Canizares O. Contact dermatitis due to the acrylic materials used in artificial nails. AMA Arch Derm. 1956;74:141-143.
- Fisher AA, Franks A, Glick H. Allergic sensitization of the skin and nails to acrylic plastic nails. J Allergy. 1957;28:84-88.
- US Food and Drug Administration. Nail care products. http://www.fda.gov/Cosmetics/ProductsIngredients/Products/ucm127068.htm. Updated October 26, 2016. Accessed December 27, 2016.
- Haughton AM, Belsito DV. Acrylate allergy induced by acrylic nails resulting in prosthesis failure. J Am Acad Dermatol. 2008;59(5 suppl):S123-S124.
- Kanerva L. Cross-reactions of multifunctional methacrylates and acrylates. Acta Odontol Scand. 2001;59:320-329.
- Tammaro A, Narcisi A, Abruzzese C, et al. Fingertip dermatitis: occupational acrylate cross reaction. Allergol Int. 2014;63:609-610.
- Kwok C, Money A, Carder M, et al. Cases of occupational dermatitis and asthma in beauticians that were reported to The Health and Occupation Research (THOR) network from 1996 to 2011. Clin Exp Dermatol. 2014;39:590-595.
- Aalto-Korte K, Alanko K, Kuuliala O, et al. Methacrylate and acrylate allergy in dental personnel. Contact Dermatitis. 2007;57:324-330.
- Molina L, Amado A, Mattei PL 4th, et al. Contact dermatitis from acrylics in a histology laboratory assistant. Dermatitis. 2009;20:E11-E12.
- Prasad Hunasehally RY, Hughes TM, Stone NM. Atypical pattern of (meth)acrylate allergic contact dermatitis in dental professionals. Br Dent J. 2012;213:223-224.
- Stingeni L, Cerulli E, Spalletti A, et al. The role of acrylic acid impurity as a sensitizing component in electrocardiogram electrodes [published online January 27, 2015]. Contact Dermatitis. 2015;73:44-48.
- Sasseville D. Acrylates in contact dermatitis. Dermatitis. 2012;23:6-16.
- Fisher AA. Cross reactions between methyl methacrylate monomer and acrylic monomers presently used in acrylic nail preparations. Contact Dermatitis. 1980;6:345-347.
- Hemmer W, Focke M, Wantke F, et al. Allergic contact dermatitis to artificial fingernails prepared from UV light-cured acrylates. J Am Acad Dermatol. 1996;35(3, pt 1):377-380.
- Teik-Jin Goon A, Bruze M, Zimerson E, et al. Contact allergy to acrylates/methacrylates in the acrylate and nail acrylics series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2007;57:21-27.
- Drucker AM, Pratt MD. Acrylate contact allergy: patient characteristics and evaluation of screening allergens. Dermatitis. 2011;22:98-101.
- Ramos L, Cabral R, Goncalo M. Allergic contact dermatitis caused by acrylates and methacrylates--a 7-year study. Contact Dermatitis. 2014;71:102-107.
- Goon AT, Isaksson M, Zimerson E, et al. Contact allergy to (meth)acrylates in the dental series in southern Sweden: simultaneous positive patch test reaction patterns and possible screening allergens. Contact Dermatitis. 2006;55:219-226.
- Isaksson M, Lindberg M, Sundberg K, et al. The development and course of patch-test reactions to 2-hydroxyethyl methacrylate and ethyleneglycol dimethacrylate. Contact Dermatitis. 2005;53:292-297.
A 28-year-old woman presented with distal onycholysis of all 10 fingernails. The patient started to notice brittleness in the first, second, and third fingernails of the right hand 2 months prior. She had a 10-year history of wearing acrylic nails and reported a history of periungual eczema. On physical examination, all 10 fingernails had distal onycholysis and there was a green discoloration of the first fingernail on the left hand. On blood analysis, thyroid-stimulating hormone and free thyroxine were within reference range. A nail clipping showed onychodystrophy and a negative periodic acid-Schiff stain.
High-risk relatives of MS patients show early signs of disease
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening. Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking.
The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors.
Fredrik Piehl, MD, PhD, is a member of the department of neurology at the Karolinska Institutet and Karolinska University Hospital, Stockholm. His comments are derived from an editorial accompanying the report by Dr. Xia and colleagues (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5126). He disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
Asymptomatic first-degree relatives of multiple sclerosis patients at high risk for developing the disease were significantly more likely to show subclinical signs of MS than were family members at lower risk, in the Genes and Environment in Multiple Sclerosis prospective cohort study. The findings were published online on Jan. 17 in JAMA Neurology.
The Genes and Environment in Multiple Sclerosis (GEMS) project is the first prospective study of populations at risk for MS and is the first detailed cross-sectional examination of higher-risk and lower-risk family members to date, according to investigators led by Zongqi Xia, MD, PhD, of Brigham and Women’s Hospital, Boston. Although the totality of evidence put together through neuroimaging and numerous clinical tests in the study indicate that individuals with the highest risk for MS have higher risk for the disease than do those with the lowest risk, simple vibration threshold testing gave the best results, Dr. Xia and his colleagues reported.
The study involved 100 neurologically asymptomatic adults aged 18-50 years who were first-degree relatives of people with MS who participated in the GEMS project during August 2012 to July 2015. These 100 comprised 41 high-risk participants from the top 10% of a Genetic and Environmental Risk Score (GERS) and 59 low-risk participants from the bottom 10% on the GERS. The GERS included genetic risk factors (HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, body mass index, history of infectious mononucleosis and migraine, and vitamin D levels.
However, because 40 of the 41 high-risk individuals were female and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex.”
To help in identifying early signs of MS, the researchers used brain MRI and optical coherence tomography and other measures of neurological function, including the Expanded Disability Status Scale, timed 25-foot walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity (JAMA Neurol. 2017 Jan 17. doi: 10.1001/jamaneurol.2016.5056).
Overall, high-risk women showed more subclinical signs of MS than did low-risk women based on an omnibus test that globally assessed the burden of neurological dysfunction by comparing the overall differences between the two groups when considering all of the measured outcomes (P = .01). However, impaired vibration perception yielded a stronger result; of 47 women (27 high-risk and 20 low-risk) tested in this manner, high-risk women showed significantly reduced vibration perception in the distal lower extremities (P = .008).
One individual in the high-risk group converted to clinically definite MS during the study. Four of the high-risk women had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one low-risk woman. The 2016 proposed consensus MRI criteria for MS diagnosis were met by two high-risk women and one low-risk woman. Radiological isolated syndrome occurred in one woman of each group, and there was a single foci of leptominengeal enhancement in three high-risk women and one low-risk woman.
The findings were limited by several factors including the small size, lack of male participants, cross-sectional nature of the study, and the fact that vibration sensitivity thresholds were in the normal range for high-risk and low-risk individuals. However, the researchers wrote that they “plan to confirm the finding of change in vibration sensitivity with a follow-up study,” and they noted that the “study highlights the important need to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”
The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
FROM JAMA NEUROLOGY
Key clinical point: Higher-risk asymptomatic female family relatives of patients with MS are more likely to have early subclinical manifestations of the disease and deserve further monitoring.
Major finding: Women at high risk for MS scored significantly higher on a composite of measured outcomes (P = .01) and on a vibration sensitivity test (P = .008), compared with lower-risk women.
Data source: A prospective, cross-sectional, cohort study of 65 adult women at risk for MS.
Disclosures: The National Institutes of Health and the National Multiple Sclerosis Society supported the study. Some of the authors reported receiving awards from the National Multiple Sclerosis Society, the American Academy of Neurology, and the National Institute of Neurological Disorders and Stroke.
January Hot Threads in ACS Communities
Want to know what your colleagues are talking about? Here are the top discussion threads in ACS Communities (all from the General Surgery community):
1. A lap appy ain’t always easy ...
3. Privileging
4. Malpractice moles
5. Safe laparoscopic entry
6. Is PID a general surgery problem?
7. Family debriefing after surgery
8. Peer-to-peer review
9. What should I do?
10. CT colonography
To join communities, log in to ACS Communities at http://acscommunities.facs.org/home, go to “Browse All Communities” near the top of any page, and click the blue “Join” button next to the community you’d like to join. If you have any questions, please send them to [email protected].
Want to know what your colleagues are talking about? Here are the top discussion threads in ACS Communities (all from the General Surgery community):
1. A lap appy ain’t always easy ...
3. Privileging
4. Malpractice moles
5. Safe laparoscopic entry
6. Is PID a general surgery problem?
7. Family debriefing after surgery
8. Peer-to-peer review
9. What should I do?
10. CT colonography
To join communities, log in to ACS Communities at http://acscommunities.facs.org/home, go to “Browse All Communities” near the top of any page, and click the blue “Join” button next to the community you’d like to join. If you have any questions, please send them to [email protected].
Want to know what your colleagues are talking about? Here are the top discussion threads in ACS Communities (all from the General Surgery community):
1. A lap appy ain’t always easy ...
3. Privileging
4. Malpractice moles
5. Safe laparoscopic entry
6. Is PID a general surgery problem?
7. Family debriefing after surgery
8. Peer-to-peer review
9. What should I do?
10. CT colonography
To join communities, log in to ACS Communities at http://acscommunities.facs.org/home, go to “Browse All Communities” near the top of any page, and click the blue “Join” button next to the community you’d like to join. If you have any questions, please send them to [email protected].
Genetic studies link JIA subtypes to adult diseases, show uniqueness of systemic disease
Two new studies of the genetic relationships between the seven designated categories of juvenile idiopathic arthritis (JIA) provide compelling support for reclassification of the categories, particularly for systemic JIA, and give evidence that some of the categories have clear equivalents in the realm of adult-onset diseases.
The International League of Associations for Rheumatology (ILAR) classification system (J Rheumatol. 2004;31:390-2) that defined the seven juvenile idiopathic arthritis (JIA) categories – systemic arthritis, oligoarticular arthritis, rheumatoid factor (RF)–negative polyarticular arthritis, RF-positive polyarticular arthritis, psoriatic arthritis (PsA), enthesitis-related arthritis (ERA), and undifferentiated arthritis – is problematic because the long-term outcome and response to treatment varies not only between subtypes but also within the subtypes, suggesting that these subgroups do not yet represent uniform groups of patients,” Wendy Thomson, PhD, professor of genetic epidemiology at the University of Manchester (England) and a senior author on both studies, explained in an interview.
“Despite the differences between the subtypes, current treatments of this disease often involve using the same drugs across all subtypes of JIA,” said Dr. Thomson, who is also deputy director of the Arthritis Research UK Centre for Genetics and Genomics at the university. “Understanding the genetic basis of the subtypes of this disease could help understand the cause of this disease and identify more appropriate treatment options [because] the current classification is largely based on clinical data and it is proposed that the addition of genetic data could improve classification.”
Interrelationships between JIA categories and adult disease
The first of these studies found that particular alleles in the human leukocyte antigen (HLA) region that have been associated with the different JIA categories strongly correlate some of the categories with one another, and that each JIA category potentially has an adult-onset counterpart based on shared HLA associations. It is the largest investigation of association of the HLA region with JIA and its categories to date, according to the researchers (Ann Rheum Dis. 2016 Dec 20. doi: 10.1136/annrheumdis-2016-210025).
In particular, the investigators demonstrated for the first time that RF-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. They also reported that RF-positive polyarthritis shares an association with adult seropositive rheumatoid arthritis and that combined data for oligoarthritis and RF-negative polyarthritis share the same association with adult seronegative RA. In addition, the researchers generated support for genetic associations between the particular JIA categories that are most commonly thought to have adult counterparts, such as ERA and adult ankylosing spondylitis (AS) as well as juvenile PsA and adult PsA.
Dr. Thomson and her coinvestigators used ImmunoChip genotype array data for 191,494 single nucleotide polymorphism (SNP) markers from the HLA region of 5,737 JIA patients and 16,403 controls in the United States, United Kingdom, Canada, Norway, and Germany to impute classical HLA alleles as well as specific amino acid positions within HLA alleles that may play an important functional role. After quality-control measures for the data were put in place, comparisons between 5,043 JIA cases and 14,390 controls showed that oligoarthritis and RF-negative polyarthritis were the most common and homogeneous JIA categories investigated (2,409 and 1,525 patients, respectively), and that they share a significant association across the HLA spectrum, meaning that they are genetically similar. When combined, the data from these two JIA categories correspond with seronegative rheumatoid arthritis in adults, while RF-positive polyarthritis on its own has an association with seropositive rheumatoid arthritis involving histidine at position 13 of the HLA-DRB1 allele. As expected, the most significant association between the ERA category and AS was for HLA-B*27. For juvenile PsA, no associations reached genome-wide level of significance, although HLA-C*0602 was modestly associated with juvenile PsA, and it is known to be associated with adult-onset PsA and is the primary HLA association in psoriasis.
“The results of this study have important implications for understanding disease pathogenesis, etiology, and potential future therapeutic strategies for JIA categories,” Dr. Thomson and her coauthors wrote, adding that “heterogeneity of JIA remains a key challenge to pediatric rheumatologists; however, these results may inform the debate on classification and help define a more biological-driven and molecular-driven classification system.”
Uniqueness of systemic JIA
In the second of the two studies, investigators from many different childhood arthritis study groups focused on systemic JIA (sJIA), also known in the past as Still’s disease. According to the authors, it is the first large-scale genomic study of sJIA ever published (Ann Rheum Dis. 2016 Dec 7. doi: 10.1136/annrheumdis-2016-210324).
“[sJIA] is characterized by prominent systemic inflammation and has a rare adult-onset counterpart; and undifferentiated arthritis includes arthritis that does not fit into any single category,” the authors wrote, adding that the “unique clinical characteristics of sJIA suggest that it is distinct from other forms of JIA, leading to the contention by some that sJIA should be separated from other forms of JIA and labeled as an autoinflammatory disease.”
The investigators carried out SNP genotyping on 982 children with sJIA in the United States, United Kingdom, Germany, Turkey, Italy, Brazil, Argentina, Canada, and Spain, along with 431 healthy children without sJIA who came from the same countries. A total of 7,579 control patients also underwent genotyping. Ultimately, 770 sJIA and 6,947 control subjects completed the study. sJIA was then compared with other JIA subtypes by using weighted genetic risk scores.
Comparison of the data sets for sJIA with those for the combined categories of RF-negative polyarticular JIA and oligoarticular JIA, as well as for the individual category of RF-positive polyarticular JIA, showed that sJIA has a distinct genetic architecture that separates it from those JIA categories, providing further evidence that sJIA should be classified separately from other forms of JIA and, potentially, treated differently as well.
According to Dr. Thomson, the finding “provides important evidence that sJIA should be considered a unique disease with its own specific disease mechanisms.” Dr. Thomson explained that “knowing more about the genetic risk factors of this disease might give a greater understanding of the disease processes involved in this condition and ultimately lead to novel therapies for this severely disabling disease.”
Funding for the first study was provided by the Wellcome Trust, the National Institutes of Health, the Doris Duke Charitable Foundation, the Medical Research Council, the Canadian Institutes of Health Research, the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Juvenile Diabetes Research Foundation International, and the Texas Scottish Rite Hospital for Children. Funding for the second study was provided by intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute, individual NIH grants, and grants from charitable foundations, advocacy organizations, and the governments of individual researchers’ countries. Dr. Thomson did not report any relevant financial disclosures; however, a number of coauthors reported potential conflicts of interest.
These two excellent multi-institutional genetic studies demonstrate once and for all the error promulgated by the International League of Associations for Rheumatology (ILAR) criteria formulated in the 1990s. Despite contrary voices, the ILAR committee grouped all childhood arthritis that was not due to sepsis or trauma as “juvenile idiopathic arthritis.” And despite the lack of clarity of the subtypes and the many cases that are “unclassifiable,” pediatric rheumatologists have continued to use these criteria in both drug trials and scientific studies.
Thomas Lehman, MD, is chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York. He has no relevant financial disclosures.
These two excellent multi-institutional genetic studies demonstrate once and for all the error promulgated by the International League of Associations for Rheumatology (ILAR) criteria formulated in the 1990s. Despite contrary voices, the ILAR committee grouped all childhood arthritis that was not due to sepsis or trauma as “juvenile idiopathic arthritis.” And despite the lack of clarity of the subtypes and the many cases that are “unclassifiable,” pediatric rheumatologists have continued to use these criteria in both drug trials and scientific studies.
Thomas Lehman, MD, is chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York. He has no relevant financial disclosures.
These two excellent multi-institutional genetic studies demonstrate once and for all the error promulgated by the International League of Associations for Rheumatology (ILAR) criteria formulated in the 1990s. Despite contrary voices, the ILAR committee grouped all childhood arthritis that was not due to sepsis or trauma as “juvenile idiopathic arthritis.” And despite the lack of clarity of the subtypes and the many cases that are “unclassifiable,” pediatric rheumatologists have continued to use these criteria in both drug trials and scientific studies.
Thomas Lehman, MD, is chief of the division of pediatric rheumatology at the Hospital for Special Surgery in New York. He has no relevant financial disclosures.
Two new studies of the genetic relationships between the seven designated categories of juvenile idiopathic arthritis (JIA) provide compelling support for reclassification of the categories, particularly for systemic JIA, and give evidence that some of the categories have clear equivalents in the realm of adult-onset diseases.
The International League of Associations for Rheumatology (ILAR) classification system (J Rheumatol. 2004;31:390-2) that defined the seven juvenile idiopathic arthritis (JIA) categories – systemic arthritis, oligoarticular arthritis, rheumatoid factor (RF)–negative polyarticular arthritis, RF-positive polyarticular arthritis, psoriatic arthritis (PsA), enthesitis-related arthritis (ERA), and undifferentiated arthritis – is problematic because the long-term outcome and response to treatment varies not only between subtypes but also within the subtypes, suggesting that these subgroups do not yet represent uniform groups of patients,” Wendy Thomson, PhD, professor of genetic epidemiology at the University of Manchester (England) and a senior author on both studies, explained in an interview.
“Despite the differences between the subtypes, current treatments of this disease often involve using the same drugs across all subtypes of JIA,” said Dr. Thomson, who is also deputy director of the Arthritis Research UK Centre for Genetics and Genomics at the university. “Understanding the genetic basis of the subtypes of this disease could help understand the cause of this disease and identify more appropriate treatment options [because] the current classification is largely based on clinical data and it is proposed that the addition of genetic data could improve classification.”
Interrelationships between JIA categories and adult disease
The first of these studies found that particular alleles in the human leukocyte antigen (HLA) region that have been associated with the different JIA categories strongly correlate some of the categories with one another, and that each JIA category potentially has an adult-onset counterpart based on shared HLA associations. It is the largest investigation of association of the HLA region with JIA and its categories to date, according to the researchers (Ann Rheum Dis. 2016 Dec 20. doi: 10.1136/annrheumdis-2016-210025).
In particular, the investigators demonstrated for the first time that RF-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. They also reported that RF-positive polyarthritis shares an association with adult seropositive rheumatoid arthritis and that combined data for oligoarthritis and RF-negative polyarthritis share the same association with adult seronegative RA. In addition, the researchers generated support for genetic associations between the particular JIA categories that are most commonly thought to have adult counterparts, such as ERA and adult ankylosing spondylitis (AS) as well as juvenile PsA and adult PsA.
Dr. Thomson and her coinvestigators used ImmunoChip genotype array data for 191,494 single nucleotide polymorphism (SNP) markers from the HLA region of 5,737 JIA patients and 16,403 controls in the United States, United Kingdom, Canada, Norway, and Germany to impute classical HLA alleles as well as specific amino acid positions within HLA alleles that may play an important functional role. After quality-control measures for the data were put in place, comparisons between 5,043 JIA cases and 14,390 controls showed that oligoarthritis and RF-negative polyarthritis were the most common and homogeneous JIA categories investigated (2,409 and 1,525 patients, respectively), and that they share a significant association across the HLA spectrum, meaning that they are genetically similar. When combined, the data from these two JIA categories correspond with seronegative rheumatoid arthritis in adults, while RF-positive polyarthritis on its own has an association with seropositive rheumatoid arthritis involving histidine at position 13 of the HLA-DRB1 allele. As expected, the most significant association between the ERA category and AS was for HLA-B*27. For juvenile PsA, no associations reached genome-wide level of significance, although HLA-C*0602 was modestly associated with juvenile PsA, and it is known to be associated with adult-onset PsA and is the primary HLA association in psoriasis.
“The results of this study have important implications for understanding disease pathogenesis, etiology, and potential future therapeutic strategies for JIA categories,” Dr. Thomson and her coauthors wrote, adding that “heterogeneity of JIA remains a key challenge to pediatric rheumatologists; however, these results may inform the debate on classification and help define a more biological-driven and molecular-driven classification system.”
Uniqueness of systemic JIA
In the second of the two studies, investigators from many different childhood arthritis study groups focused on systemic JIA (sJIA), also known in the past as Still’s disease. According to the authors, it is the first large-scale genomic study of sJIA ever published (Ann Rheum Dis. 2016 Dec 7. doi: 10.1136/annrheumdis-2016-210324).
“[sJIA] is characterized by prominent systemic inflammation and has a rare adult-onset counterpart; and undifferentiated arthritis includes arthritis that does not fit into any single category,” the authors wrote, adding that the “unique clinical characteristics of sJIA suggest that it is distinct from other forms of JIA, leading to the contention by some that sJIA should be separated from other forms of JIA and labeled as an autoinflammatory disease.”
The investigators carried out SNP genotyping on 982 children with sJIA in the United States, United Kingdom, Germany, Turkey, Italy, Brazil, Argentina, Canada, and Spain, along with 431 healthy children without sJIA who came from the same countries. A total of 7,579 control patients also underwent genotyping. Ultimately, 770 sJIA and 6,947 control subjects completed the study. sJIA was then compared with other JIA subtypes by using weighted genetic risk scores.
Comparison of the data sets for sJIA with those for the combined categories of RF-negative polyarticular JIA and oligoarticular JIA, as well as for the individual category of RF-positive polyarticular JIA, showed that sJIA has a distinct genetic architecture that separates it from those JIA categories, providing further evidence that sJIA should be classified separately from other forms of JIA and, potentially, treated differently as well.
According to Dr. Thomson, the finding “provides important evidence that sJIA should be considered a unique disease with its own specific disease mechanisms.” Dr. Thomson explained that “knowing more about the genetic risk factors of this disease might give a greater understanding of the disease processes involved in this condition and ultimately lead to novel therapies for this severely disabling disease.”
Funding for the first study was provided by the Wellcome Trust, the National Institutes of Health, the Doris Duke Charitable Foundation, the Medical Research Council, the Canadian Institutes of Health Research, the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Juvenile Diabetes Research Foundation International, and the Texas Scottish Rite Hospital for Children. Funding for the second study was provided by intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute, individual NIH grants, and grants from charitable foundations, advocacy organizations, and the governments of individual researchers’ countries. Dr. Thomson did not report any relevant financial disclosures; however, a number of coauthors reported potential conflicts of interest.
Two new studies of the genetic relationships between the seven designated categories of juvenile idiopathic arthritis (JIA) provide compelling support for reclassification of the categories, particularly for systemic JIA, and give evidence that some of the categories have clear equivalents in the realm of adult-onset diseases.
The International League of Associations for Rheumatology (ILAR) classification system (J Rheumatol. 2004;31:390-2) that defined the seven juvenile idiopathic arthritis (JIA) categories – systemic arthritis, oligoarticular arthritis, rheumatoid factor (RF)–negative polyarticular arthritis, RF-positive polyarticular arthritis, psoriatic arthritis (PsA), enthesitis-related arthritis (ERA), and undifferentiated arthritis – is problematic because the long-term outcome and response to treatment varies not only between subtypes but also within the subtypes, suggesting that these subgroups do not yet represent uniform groups of patients,” Wendy Thomson, PhD, professor of genetic epidemiology at the University of Manchester (England) and a senior author on both studies, explained in an interview.
“Despite the differences between the subtypes, current treatments of this disease often involve using the same drugs across all subtypes of JIA,” said Dr. Thomson, who is also deputy director of the Arthritis Research UK Centre for Genetics and Genomics at the university. “Understanding the genetic basis of the subtypes of this disease could help understand the cause of this disease and identify more appropriate treatment options [because] the current classification is largely based on clinical data and it is proposed that the addition of genetic data could improve classification.”
Interrelationships between JIA categories and adult disease
The first of these studies found that particular alleles in the human leukocyte antigen (HLA) region that have been associated with the different JIA categories strongly correlate some of the categories with one another, and that each JIA category potentially has an adult-onset counterpart based on shared HLA associations. It is the largest investigation of association of the HLA region with JIA and its categories to date, according to the researchers (Ann Rheum Dis. 2016 Dec 20. doi: 10.1136/annrheumdis-2016-210025).
In particular, the investigators demonstrated for the first time that RF-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. They also reported that RF-positive polyarthritis shares an association with adult seropositive rheumatoid arthritis and that combined data for oligoarthritis and RF-negative polyarthritis share the same association with adult seronegative RA. In addition, the researchers generated support for genetic associations between the particular JIA categories that are most commonly thought to have adult counterparts, such as ERA and adult ankylosing spondylitis (AS) as well as juvenile PsA and adult PsA.
Dr. Thomson and her coinvestigators used ImmunoChip genotype array data for 191,494 single nucleotide polymorphism (SNP) markers from the HLA region of 5,737 JIA patients and 16,403 controls in the United States, United Kingdom, Canada, Norway, and Germany to impute classical HLA alleles as well as specific amino acid positions within HLA alleles that may play an important functional role. After quality-control measures for the data were put in place, comparisons between 5,043 JIA cases and 14,390 controls showed that oligoarthritis and RF-negative polyarthritis were the most common and homogeneous JIA categories investigated (2,409 and 1,525 patients, respectively), and that they share a significant association across the HLA spectrum, meaning that they are genetically similar. When combined, the data from these two JIA categories correspond with seronegative rheumatoid arthritis in adults, while RF-positive polyarthritis on its own has an association with seropositive rheumatoid arthritis involving histidine at position 13 of the HLA-DRB1 allele. As expected, the most significant association between the ERA category and AS was for HLA-B*27. For juvenile PsA, no associations reached genome-wide level of significance, although HLA-C*0602 was modestly associated with juvenile PsA, and it is known to be associated with adult-onset PsA and is the primary HLA association in psoriasis.
“The results of this study have important implications for understanding disease pathogenesis, etiology, and potential future therapeutic strategies for JIA categories,” Dr. Thomson and her coauthors wrote, adding that “heterogeneity of JIA remains a key challenge to pediatric rheumatologists; however, these results may inform the debate on classification and help define a more biological-driven and molecular-driven classification system.”
Uniqueness of systemic JIA
In the second of the two studies, investigators from many different childhood arthritis study groups focused on systemic JIA (sJIA), also known in the past as Still’s disease. According to the authors, it is the first large-scale genomic study of sJIA ever published (Ann Rheum Dis. 2016 Dec 7. doi: 10.1136/annrheumdis-2016-210324).
“[sJIA] is characterized by prominent systemic inflammation and has a rare adult-onset counterpart; and undifferentiated arthritis includes arthritis that does not fit into any single category,” the authors wrote, adding that the “unique clinical characteristics of sJIA suggest that it is distinct from other forms of JIA, leading to the contention by some that sJIA should be separated from other forms of JIA and labeled as an autoinflammatory disease.”
The investigators carried out SNP genotyping on 982 children with sJIA in the United States, United Kingdom, Germany, Turkey, Italy, Brazil, Argentina, Canada, and Spain, along with 431 healthy children without sJIA who came from the same countries. A total of 7,579 control patients also underwent genotyping. Ultimately, 770 sJIA and 6,947 control subjects completed the study. sJIA was then compared with other JIA subtypes by using weighted genetic risk scores.
Comparison of the data sets for sJIA with those for the combined categories of RF-negative polyarticular JIA and oligoarticular JIA, as well as for the individual category of RF-positive polyarticular JIA, showed that sJIA has a distinct genetic architecture that separates it from those JIA categories, providing further evidence that sJIA should be classified separately from other forms of JIA and, potentially, treated differently as well.
According to Dr. Thomson, the finding “provides important evidence that sJIA should be considered a unique disease with its own specific disease mechanisms.” Dr. Thomson explained that “knowing more about the genetic risk factors of this disease might give a greater understanding of the disease processes involved in this condition and ultimately lead to novel therapies for this severely disabling disease.”
Funding for the first study was provided by the Wellcome Trust, the National Institutes of Health, the Doris Duke Charitable Foundation, the Medical Research Council, the Canadian Institutes of Health Research, the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Juvenile Diabetes Research Foundation International, and the Texas Scottish Rite Hospital for Children. Funding for the second study was provided by intramural research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute, individual NIH grants, and grants from charitable foundations, advocacy organizations, and the governments of individual researchers’ countries. Dr. Thomson did not report any relevant financial disclosures; however, a number of coauthors reported potential conflicts of interest.
FROM ANNALS OF THE RHEUMATIC DISEASES
Rituximab vanquished MRD in mantle cell lymphoma
SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.
Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m2), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.
The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.
Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.
After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.
Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.
Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.
SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.
Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m2), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.
The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.
Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.
After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.
Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.
Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.
SAN DIEGO – Rituximab can at least temporarily vanquish minimal residual disease (MRD) in mantle cell lymphoma (MCL) patients who relapse after induction therapy and autologous stem cell transplantation (ASCT), researchers reported at the annual meeting of the American Society of Hematology.
Of 58 patients whose MCL relapsed after induction therapy and ASCT, 82% converted back to an MRD-negative state after receiving 4 weekly doses of rituximab (375 mg/m2), Arne Kolstad, MD, PhD, and his associates. The data “strongly suggest that preemptive rituximab treatment delayed clinical relapse in MCL,” they wrote in their abstract. They recommended molecular and clinical monitoring after ASCT, not only “as an alternative to maintenance therapy for all MCL patients” but to identify MRD-positive candidates for clinical trials.
The study was an analysis of the Nordic Lymphoma Group phase II MCL2 and MCL3 trials (NTC 00514475), in which patients received six alternating cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and R-Ara-C (rituximab-cytarabine). followed by high-dose ASCT. In MCL3, responders who fell short of complete remission also received intensification with yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) 1 week before treatment with BEAM/C (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide). Patients were evaluated 2-3 months after completing ASCT, and then every 6 months for 5 years or until relapse. Survivors were followed for a median of 8.5 years, noted Dr. Kolstad, who is with Oslo University Hospital in Norway.
Among 183 patients who underwent polymerase chain reaction–based testing for markers of MRD, median time to molecular relapse was 55 months. However, the relapse-free survival curve did not plateau – patients in all risk groups continued to relapse 5-10 years after undergoing ASCT, the researchers said. “Hence, it is fair to consider MCL as a chronic incurable lymphoma entity, and novel approaches will be necessary to change the natural course of this disease,” they wrote.
After controlling for potential confounders, significant predictors of molecular relapse included high MCL international prognostic index at diagnosis (hazard ratio, 1.9; 95% confidence interval 1.4-2.7; P = .0001) and detection of MRD before patients underwent ASCT (HR, 2.5; 95% CI, 1.5-4.1; P = .0005). Minimal residual disease predicted clinical relapse and shorter survival (P less than .001 for both associations). In contrast, the 86 patients who remained in continuous molecular remission had a 76% chance of having at least a 10-year clinical remission, the investigators said.
Minimal residual disease was assessed by testing bone marrow and blood samples with combined standard nested and quantitative real-time polymerase chain reaction (PCR) for Bcl-1 or IgH rearrangement. They defined molecular relapse as conversion from a negative to a positive result on standard nested PCR, or, for patients who were MRD positive after ASCT, as a more than fivefold rise in real-time quantitative PCR levels in two consecutive bone marrow samples.
Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.
AT ASH 2016
Key clinical point:
Major finding: Among 58 patients who relapsed after induction therapy and autologous stem cell transplantation, 82% converted back to an MRD-negative state with 4 weekly doses of rituximab (375 mg/m2).
Data source: A study of 183 patients with mantle cell lymphoma from the Nordic MCL2 and MCL3 trials.
Disclosures: Oslo University sponsored the trials. Dr. Kolstad reported ties to Nordic Nanovector, Bayer Schering Pharma, Merck, and Roche.
LMWH trumps unfractionated heparin in reducing posttrauma thrombotic events
HOLLYWOOD, FLA. – Low-molecular-weight heparin (LMWH) decreased the risk of venous thromboembolism in trauma patients significantly more than did unfractionated heparin, a large state database review has found.
It also was associated with a 37% decrease in overall mortality, compared with unfractionated heparin, Benjamin Jacobs, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
He extracted data describing thromboembolism prophylaxis among 37,868 trauma patients included in the Michigan Trauma Quality Improvement Program from 2012 to 2014. The patients were treated at 23 hospitals around the state. They received either unfractionated or LMWH as their only clot-preventing protocol.
The primary outcomes of the study were reductions in the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary thrombosis (PT), and mortality.
LMWH was given at either 40 mg every day or 30 mg twice a day. The comparator was unfractionated heparin at 5,000 U either two or three times a day.
The preferred method was LMWH, which 83% of patients received, compared with 17% who got the unfractionated heparin. Most patients who got LMWH received the 40 mg/day dose (70%). Most who got unfractionated heparin received 5,000 U three times a day (87%).
Both types of heparin reduced the risk of all thromboembolic outcomes, and both doses of LMWH significantly reduced the risks. However, the 40 mg/day dose was significantly more effective than the twice-daily 30-mg dose in reducing the risk of VTE and DVT. Risk reductions for PT and mortality were not significantly different between the doses.
Overall, compared with unfractionated heparin, LMWH decreased the risk of VTE by 33%; of PT by 48%; and of DVT by 27%. It also conferred a significant mortality benefit, reducing the risk of death by 37%, compared with the unfractionated type
When Dr. Jacobs grouped the patients according to Injury Severity Score (ISS), he saw a consistently higher benefit among patients with lower scores. For example, LMWH significantly reduced the risk of PT by 59% in patients with an ISS of 5-14. In those with an ISS of 25 or higher, the drug was associated with a 20% increased risk, although that wasn’t statistically significant.
There was a similar finding in DVT. LMWH reduced the risk by 18% in those with an ISS of 5-15, and by 50% among those with an score of 16-24 – both significant reductions. Among those with an ISS of at least 25, the risk was 18% higher, although, again, it was not a significant finding.
Curiously, the mortality benefit was stronger among sicker patients. The benefit was nonsignificant among those with an ISS of less than 25 but for those above 25, the mortality risk reduction was a significant 45%.
Dr Jacobs had no financial disclosures.
[email protected]
On Twitter @alz_gal
HOLLYWOOD, FLA. – Low-molecular-weight heparin (LMWH) decreased the risk of venous thromboembolism in trauma patients significantly more than did unfractionated heparin, a large state database review has found.
It also was associated with a 37% decrease in overall mortality, compared with unfractionated heparin, Benjamin Jacobs, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
He extracted data describing thromboembolism prophylaxis among 37,868 trauma patients included in the Michigan Trauma Quality Improvement Program from 2012 to 2014. The patients were treated at 23 hospitals around the state. They received either unfractionated or LMWH as their only clot-preventing protocol.
The primary outcomes of the study were reductions in the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary thrombosis (PT), and mortality.
LMWH was given at either 40 mg every day or 30 mg twice a day. The comparator was unfractionated heparin at 5,000 U either two or three times a day.
The preferred method was LMWH, which 83% of patients received, compared with 17% who got the unfractionated heparin. Most patients who got LMWH received the 40 mg/day dose (70%). Most who got unfractionated heparin received 5,000 U three times a day (87%).
Both types of heparin reduced the risk of all thromboembolic outcomes, and both doses of LMWH significantly reduced the risks. However, the 40 mg/day dose was significantly more effective than the twice-daily 30-mg dose in reducing the risk of VTE and DVT. Risk reductions for PT and mortality were not significantly different between the doses.
Overall, compared with unfractionated heparin, LMWH decreased the risk of VTE by 33%; of PT by 48%; and of DVT by 27%. It also conferred a significant mortality benefit, reducing the risk of death by 37%, compared with the unfractionated type
When Dr. Jacobs grouped the patients according to Injury Severity Score (ISS), he saw a consistently higher benefit among patients with lower scores. For example, LMWH significantly reduced the risk of PT by 59% in patients with an ISS of 5-14. In those with an ISS of 25 or higher, the drug was associated with a 20% increased risk, although that wasn’t statistically significant.
There was a similar finding in DVT. LMWH reduced the risk by 18% in those with an ISS of 5-15, and by 50% among those with an score of 16-24 – both significant reductions. Among those with an ISS of at least 25, the risk was 18% higher, although, again, it was not a significant finding.
Curiously, the mortality benefit was stronger among sicker patients. The benefit was nonsignificant among those with an ISS of less than 25 but for those above 25, the mortality risk reduction was a significant 45%.
Dr Jacobs had no financial disclosures.
[email protected]
On Twitter @alz_gal
HOLLYWOOD, FLA. – Low-molecular-weight heparin (LMWH) decreased the risk of venous thromboembolism in trauma patients significantly more than did unfractionated heparin, a large state database review has found.
It also was associated with a 37% decrease in overall mortality, compared with unfractionated heparin, Benjamin Jacobs, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
He extracted data describing thromboembolism prophylaxis among 37,868 trauma patients included in the Michigan Trauma Quality Improvement Program from 2012 to 2014. The patients were treated at 23 hospitals around the state. They received either unfractionated or LMWH as their only clot-preventing protocol.
The primary outcomes of the study were reductions in the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary thrombosis (PT), and mortality.
LMWH was given at either 40 mg every day or 30 mg twice a day. The comparator was unfractionated heparin at 5,000 U either two or three times a day.
The preferred method was LMWH, which 83% of patients received, compared with 17% who got the unfractionated heparin. Most patients who got LMWH received the 40 mg/day dose (70%). Most who got unfractionated heparin received 5,000 U three times a day (87%).
Both types of heparin reduced the risk of all thromboembolic outcomes, and both doses of LMWH significantly reduced the risks. However, the 40 mg/day dose was significantly more effective than the twice-daily 30-mg dose in reducing the risk of VTE and DVT. Risk reductions for PT and mortality were not significantly different between the doses.
Overall, compared with unfractionated heparin, LMWH decreased the risk of VTE by 33%; of PT by 48%; and of DVT by 27%. It also conferred a significant mortality benefit, reducing the risk of death by 37%, compared with the unfractionated type
When Dr. Jacobs grouped the patients according to Injury Severity Score (ISS), he saw a consistently higher benefit among patients with lower scores. For example, LMWH significantly reduced the risk of PT by 59% in patients with an ISS of 5-14. In those with an ISS of 25 or higher, the drug was associated with a 20% increased risk, although that wasn’t statistically significant.
There was a similar finding in DVT. LMWH reduced the risk by 18% in those with an ISS of 5-15, and by 50% among those with an score of 16-24 – both significant reductions. Among those with an ISS of at least 25, the risk was 18% higher, although, again, it was not a significant finding.
Curiously, the mortality benefit was stronger among sicker patients. The benefit was nonsignificant among those with an ISS of less than 25 but for those above 25, the mortality risk reduction was a significant 45%.
Dr Jacobs had no financial disclosures.
[email protected]
On Twitter @alz_gal
AT THE EAST ANNUAL SCIENTIFIC ASSEMBLY
Key clinical point:
Major finding: Overall mortality was reduced by 37% with LMWH, compared with unfractionated heparin.
Data source: The review comprised 37,868 patients included in the Michigan Trauma Quality Improvement Program.
Disclosures: Dr. Jacobs had no financial disclosures.