NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.

She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.

Bruce Jancin/MDedge News

Optimizing perioperative pain management pathways

As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).

Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.

Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).

Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).

Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.

A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.

That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.

Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).

“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
 

Perioperative management of DMARDs

Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).

“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.

Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.

In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.

Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
 

Low-dose aspirin for VTE prophylaxis

“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.

She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.

The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.

The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).

Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
 

Preoperative prediction of postop delirium

Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.

They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.

“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.

In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).

Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).

“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
 

When is postop fever a concern?

Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.

Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).

A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.

The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).

In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
 

Optimal time window for hip fracture surgery

AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.

But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.

The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.

For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).

But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.

Dr. Wallace reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.

She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.

Bruce Jancin/MDedge News

Optimizing perioperative pain management pathways

As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).

Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.

Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).

Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).

Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.

A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.

That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.

Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).

“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
 

Perioperative management of DMARDs

Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).

“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.

Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.

In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.

Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
 

Low-dose aspirin for VTE prophylaxis

“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.

She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.

The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.

The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).

Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
 

Preoperative prediction of postop delirium

Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.

They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.

“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.

In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).

Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).

“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
 

When is postop fever a concern?

Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.

Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).

A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.

The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).

In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
 

Optimal time window for hip fracture surgery

AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.

But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.

The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.

For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).

But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.

Dr. Wallace reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

NEW ORLEANS – Comanagement of orthopedic inpatients by an internist or hospitalist can improve outcomes in myriad ways, Mary Anderson Wallace, MD, said at the annual meeting of the American College of Physicians.

She focused on patients undergoing total hip or knee arthroplasty (THA/TKA). In 2014, there were 400,000 of them under Medicare alone, accounting for $7 billion in hospitalization costs and nearly as much again in the cost of related postdischarge care.

Bruce Jancin/MDedge News

Optimizing perioperative pain management pathways

As of 2015, orthopedists ranked as the third highest prescribers of opioids. Impressively, a retrospective cohort study of 641,941 opioid-naive, privately insured patients undergoing 1 of 11 types of surgery demonstrated that TKA was associated with a 5.1-fold increased risk for subsequent chronic opioid use in the first year after surgery, compared with 18 million opioid-naive nonsurgical controls. Indeed, TKA was the highest-risk of the 11 surgical procedures examined (JAMA Intern Med. 2016 Sep 1;176[9]:1286-93).

Another study that points to a need to develop best practices for opioid prescribing in orthopedic surgery – and other types of surgery as well – was a systematic review of six studies of patients who received prescription opioid analgesics in conjunction with seven types of surgery.

Opioid oversupply was identified as a clear problem: 67%-92% of patients in the six studies reported unused opioids. Up to 71% of opioid tablets went unused, mainly because patients felt they’d achieved adequate pain control and didn’t need them. Rates of safe disposal of unused opioids were in the single digits, suggesting that overprescribing provides a large potential reservoir of opioids that can be diverted to nonmedical use (JAMA Surg. 2017 Nov 1;152[11]:1066-71).

Moreover, a recent retrospective study of more than 1 million opioid-naive patients undergoing surgery showed that 56% of them received postoperative opioids. And each additional week of use was associated with a 44% increase in the relative risk of the composite endpoint of opioid dependence, abuse, or overdose. Duration of opioid use was a stronger predictor of this adverse outcome than was dosage (BMJ. 2018 Jan 17;360:j5790).

Other studies have shown that multimodal analgesia is utilized in only 25%-50% of surgical patients, even though it is considered the standard of care. Only 20% of patients undergoing THA/TKA receive peripheral nerve and neuraxial blocks. So, there is an opportunity for optimization of perioperative pain management pathways in orthopedic surgery patients, including avoidance of unnecessary p.r.n. prescribing, to favorably impact the national opioid epidemic, Dr. Wallace observed.

A surprise benefit of multimodal pain management that includes acetaminophen and a nonsteroidal anti-inflammatory agent is that it markedly reduces the incidence of postoperative fevers after total joint arthroplasty, compared with opioid-based pain management.

That was demonstrated in a retrospective study of 2,417 THA/TKAs in which multimodal pain management was used, and 1,484 procedures that relied on opioid-based pain relief. All of the operations were performed by the same three orthopedic surgeons. Only 5% of patients in the multimodal pain management group developed a fever greater than 38.5 degrees Celsius during the first 5 postoperative days, compared with 25% of those in the opioid-based analgesia group.

Moreover, an infectious disease workup was ordered in 2% of the multimodal analgesia group, versus 10% in the opioid-based pain management cohort, with no difference in the positive workup rates between the two groups (Clin Orthop Relat Res. 2014 May;472[5]:1489-95).

“It’s interesting that multimodal pain management has the side effect of putting you in a better position to practice high-value care, with less fever and fewer infectious disease workups,” Dr. Wallace said.
 

Perioperative management of DMARDs

Recent joint guidelines from the American College of Rheumatology and American Association of Hip and Knee Surgeons specifically address this issue in patients undergoing elective joint replacement (Arthritis Rheumatol. 2017 Aug;69[8]:1538-51).

“The quality of evidence isn’t high, but at least it’s a starting point,” Dr. Wallace said.

Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and other rheumatic diseases who are on methotrexate or other nonbiologic DMARDs should be maintained on their current dose, according to the guidelines.

In contrast, all biologic agents should be withheld prior to surgery, which should be scheduled to coincide with the end of the dosing cycle for that specific biologic. The biologic agent should be resumed only once adequate wound healing has occurred, typically about 14 days post-THA/TKA.

Patients on daily glucocorticoids should continue on their current dose; supraphysiologic stress dosing is to be avoided.
 

Low-dose aspirin for VTE prophylaxis

“It seems like nothing has been such an enduring controversy in the comanagement literature as the question of whether aspirin is an effective prophylactic agent for prevention of DVT post THA/TKA,” according to Dr. Wallace.

She noted that in the space of just 4 years between the eighth and ninth editions of the American College of Chest Physician guidelines, that organization underwent a 180-degree reversal on the issue – whipsawing from a grade 1A recommendation against aspirin in 2008 to a 1B recommendation for it in 2012.

The literature is increasingly supportive of the use of aspirin for venous thromboembolism (VTE) prophylaxis in low-risk THA/TKA patients. Separate guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the Surgical Care Improvement Project, as well as the chest physicians, support the practice.

The hitch is that there is as yet no single validated risk-stratification protocol. AAOS recommends 325 mg of aspirin twice daily for 6 weeks. But a prospective crossover study of more than 4,600 total joint arthroplasty patients conducted by investigators at Thomas Jefferson University in Philadelphia showed that 81 mg BID for 4 weeks was just as effective as was 325 mg b.i.d., albeit with an incidence of GI bleeding that to their surprise wasn’t significantly lower (J Bone Joint Surg Am. 2017 Jan 18;99[2]:91-8).

Dr. Wallace anticipates definitive answers on VTE prophylaxis to come from the ongoing Patient-Centered Outcomes Research Institute-supported PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement) trial. In that study, roughly 25,000 patients undergoing THA/TKA are being randomized to prophylactic aspirin at 81 mg b.i.d., warfarin at an International Normalized Ratio of 2.0, or rivaroxaban (Xarelto). Endpoints include mortality, VTE, and bleeding. Results are expected in 2021.
 

Preoperative prediction of postop delirium

Unrecognized preoperative cognitive impairment in older patients without dementia who are undergoing THA/TKA is a common and powerful risk factor for postop delirium and other complications, as demonstrated recently by investigators at Harvard University and affiliated hospitals.

They had 211 patients aged 65 or older, none with known dementia, take the Mini-Cog screening test prior to their surgery. Fully 24% had probable cognitive impairment as reflected in a score of 2 or less out of a possible 5 points on this simple test, which consists of a three-word recall and clock drawing.

“I was very surprised at this high rate. These are patients who are at risk for delirium in the hospital when you’re taking care of them,” Dr. Wallace observed.

In the Harvard study, the incidence of postop delirium was 21% in patients with a Mini-Cog score of 2 or less, compared with 7% who scored 3-5, for an odds ratio of 4.5 in an age-adjusted multivariate analysis. Moreover, 67% of the low scorers were discharged somewhere other than home, in contrast to 34% of patients with a preop Mini-Cog score of 3-5, for an adjusted 3.9-fold increased risk. The group with a Mini-Cog score of 2 or less also had a significantly longer hospital length of stay (Anesthesiology. 2017 Nov;127[5]:765-74).

Perioperative gabapentin is often added to the medication regimen of older surgical patients to reduce postop delirium. The latest evidence indicates that doesn’t work, as demonstrated in a recent 697-patient randomized trial. The incidence of delirium during the first 3 days post surgery as measured by the Confusion Assessment Method was 22.4% in patients randomized to 900 mg of gabapentin per day, and 20.8% with placebo. Nearly 200 participants had THA or TKA, and in that subgroup, there was an even stronger – albeit still not statistically significant – trend for a higher delirium rate with gabapentin than with placebo (Anesthesiology. 2017 Oct.127[4]:633-44).

“Think twice about adding gabapentin to the pain regimen for THA/TKA/spine patients for the purpose of preventing postop delirium,” she advised.
 

When is postop fever a concern?

Up to half of patients develop fever early after THA/TKA. In most cases, this is a self-limited ancillary effect of cytokine release, with the temperature peaking on postop day 1-2.

Three strong predictors of a positive infectious disease workup are fever after postop day 3, with an associated 23.3-fold increased risk; multiple days of fever, with an odds ratio of 8.6; and a maximum temperature greater than 39.0 degrees Celsius, with a 2.4-fold increased risk. In this 7-year-old study, the cost of infectious disease workup per change in patient management was a hefty $8,209 (J Arthroplasty. 2010 Sep;25[6 Suppl]:43-8).

A retrospective study of nearly 125,000 THA/TKA patients in the American College of Surgeons National Surgical Quality Improvement Program database has important implications for clinical surveillance for postop adverse events. Stroke occurred early, on median postop day 1. The median time of acute MI and pulmonary embolism was postop day 3, and pneumonia day 4.

The key take-home message was that the median time to DVT was postop day 6, by which point most patients had been discharged. Thus, 60% of postoperative DVTs occurred after discharge. And the time to diagnosis of DVT differed markedly by surgical procedure: The median day of diagnosis was day 5 in TKA patients, compared with day 13 for THA patients. Sixty-eight percent of urinary tract infections occurred post discharge. Sepsis occurred on median day 10 post surgery, surgical site infections on day 17 (Clin Orthop Relat Res. 2017 Dec;475[12]:2952-9).

In light of ever-shortening hospital lengths of stay, Dr. Wallace noted, the findings underscore the importance of comprehensive predischarge patient counseling.
 

Optimal time window for hip fracture surgery

AAOS guidelines recommend that hip fracture surgery should take place within 48 hours, assuming medical comorbidities are stabilized, because complication rates go up with longer wait times.

But that is controversial. A University of Toronto retrospective cohort study of 42,430 adults with hip fracture treated at 72 Canadian hospitals during 2009-2014 found that the inflection point was 24 hours. Among 13,731 patients whose elapsed time from hospital arrival to surgery was 24 hours or less, 30-day mortality was 5.8%, significantly less than the 6.5% rate in an equal number of propensity score–matched patients with a longer wait time.

The 90- and 365-day mortality rates in the patients who received surgery within 24 hours were 10.7% and 19.3%, both significantly lower than the 12.0% and 21.6% figures in patients with longer wait times.

For the 30-day composite outcome of death, myocardial infarction, pulmonary embolism, DVT, or pneumonia, the rates were 10.1% and 12.2% – again, statistically significant and clinically meaningful. The 90- and 365-day composite outcomes followed suit (JAMA. 2017 Nov 28;318[20]:1994-2003).

But the Canadian study won’t be the final word. The ongoing international multicenter HIP ATTACK (Hip Fracture Accelerated Surgical Treatment and Care Track) trial is comparing outcomes in 3,000 patients randomized to hip fracture surgery within 6 hours versus 24 hours. Endpoints include mortality, myocardial infarction, pulmonary embolism, pneumonia, stroke, sepsis, and life-threatening and major bleeding.

Dr. Wallace reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

At birth, this now 18-year-old man had what he was told was “only a birthmark.” In the years since, the lesion has darkened and become increasingly well-defined and raised. It is occasionally irritated.

His parents deny any history of seizures, skeletal problems, vision problems, or developmental disabilities in the patient or the family. All parties want the lesion removed.

EXAMINATION
A contiguous linear collection of brown-to-tan papules and nodules runs entirely across the left upper chest, ending on the left shoulder. It measures about 1 cm in width. On closer examination, many of the marks appear to be a mix of milia and comedones.

No similar lesions are seen elsewhere, and the patient’s type IV skin appears normal in all other respects.

What is the diagnosis?

• Sebaceous
• Apocrine
• Eccrine
• Follicular
• Keratinocytic.

The significance of the linear configuration is that in up to one-third of patients another organ system (eg, brain, eyes, bone) will be affected. Associated neurologic problems include seizures and intellectual disability, which are caused by a variety of neuropathologic lesions.

Other forms of epidermal nevi include nevus comedonicus (associated with cataracts) and inflammatory linear verrucous epidermal nevus (ILVEN). Most often seen in early childhood on the limbs, ILVEN accounts for about 5% of all epidermal nevi.

The case patient appeared to have a mixed form, composed of epidermal and comedonal elements. Fortunately, he did not have any other associated abnormalities.

Other items in the differential include lichen striatus, wart, and koebnerized psoriasis.

Treatment for LEN is problematic, due to not only pain and scarring but also the loss of normal pigment. Options include laser, dermabrasion, and surgery. Smaller lesions can simply be excised.

TAKE-HOME LEARNING POINTS

• Linear epidermal nevi (LEN) are benign, unusual, congenital, hamartomatous tumors of embryonal ectodermal origin, which mostly manifest above the waist (ie, shoulders, trunk) in a linear configuration.
• LEN are classified according to their predominant structural element (sebaceous, eccrine, apocrine, follicular, keratinocytic).
• About one-third of all cases involve other organs, including the brain, eyes, or skeleton.
• The differential for LEN includes wart, koebnerized psoriasis, and lichen striatus.
• Treatment can be problematic, but options include laser, dermabrasion, and surgery.

At birth, this now 18-year-old man had what he was told was “only a birthmark.” In the years since, the lesion has darkened and become increasingly well-defined and raised. It is occasionally irritated.

His parents deny any history of seizures, skeletal problems, vision problems, or developmental disabilities in the patient or the family. All parties want the lesion removed.

EXAMINATION
A contiguous linear collection of brown-to-tan papules and nodules runs entirely across the left upper chest, ending on the left shoulder. It measures about 1 cm in width. On closer examination, many of the marks appear to be a mix of milia and comedones.

No similar lesions are seen elsewhere, and the patient’s type IV skin appears normal in all other respects.

What is the diagnosis?

• Sebaceous
• Apocrine
• Eccrine
• Follicular
• Keratinocytic.

The significance of the linear configuration is that in up to one-third of patients another organ system (eg, brain, eyes, bone) will be affected. Associated neurologic problems include seizures and intellectual disability, which are caused by a variety of neuropathologic lesions.

Other forms of epidermal nevi include nevus comedonicus (associated with cataracts) and inflammatory linear verrucous epidermal nevus (ILVEN). Most often seen in early childhood on the limbs, ILVEN accounts for about 5% of all epidermal nevi.

The case patient appeared to have a mixed form, composed of epidermal and comedonal elements. Fortunately, he did not have any other associated abnormalities.

Other items in the differential include lichen striatus, wart, and koebnerized psoriasis.

Treatment for LEN is problematic, due to not only pain and scarring but also the loss of normal pigment. Options include laser, dermabrasion, and surgery. Smaller lesions can simply be excised.

TAKE-HOME LEARNING POINTS

• Linear epidermal nevi (LEN) are benign, unusual, congenital, hamartomatous tumors of embryonal ectodermal origin, which mostly manifest above the waist (ie, shoulders, trunk) in a linear configuration.
• LEN are classified according to their predominant structural element (sebaceous, eccrine, apocrine, follicular, keratinocytic).
• About one-third of all cases involve other organs, including the brain, eyes, or skeleton.
• The differential for LEN includes wart, koebnerized psoriasis, and lichen striatus.
• Treatment can be problematic, but options include laser, dermabrasion, and surgery.

At birth, this now 18-year-old man had what he was told was “only a birthmark.” In the years since, the lesion has darkened and become increasingly well-defined and raised. It is occasionally irritated.

His parents deny any history of seizures, skeletal problems, vision problems, or developmental disabilities in the patient or the family. All parties want the lesion removed.

EXAMINATION
A contiguous linear collection of brown-to-tan papules and nodules runs entirely across the left upper chest, ending on the left shoulder. It measures about 1 cm in width. On closer examination, many of the marks appear to be a mix of milia and comedones.

No similar lesions are seen elsewhere, and the patient’s type IV skin appears normal in all other respects.

What is the diagnosis?

• Sebaceous
• Apocrine
• Eccrine
• Follicular
• Keratinocytic.

The significance of the linear configuration is that in up to one-third of patients another organ system (eg, brain, eyes, bone) will be affected. Associated neurologic problems include seizures and intellectual disability, which are caused by a variety of neuropathologic lesions.

Other forms of epidermal nevi include nevus comedonicus (associated with cataracts) and inflammatory linear verrucous epidermal nevus (ILVEN). Most often seen in early childhood on the limbs, ILVEN accounts for about 5% of all epidermal nevi.

The case patient appeared to have a mixed form, composed of epidermal and comedonal elements. Fortunately, he did not have any other associated abnormalities.

Other items in the differential include lichen striatus, wart, and koebnerized psoriasis.

Treatment for LEN is problematic, due to not only pain and scarring but also the loss of normal pigment. Options include laser, dermabrasion, and surgery. Smaller lesions can simply be excised.

TAKE-HOME LEARNING POINTS

• Linear epidermal nevi (LEN) are benign, unusual, congenital, hamartomatous tumors of embryonal ectodermal origin, which mostly manifest above the waist (ie, shoulders, trunk) in a linear configuration.
• LEN are classified according to their predominant structural element (sebaceous, eccrine, apocrine, follicular, keratinocytic).
• About one-third of all cases involve other organs, including the brain, eyes, or skeleton.
• The differential for LEN includes wart, koebnerized psoriasis, and lichen striatus.
• Treatment can be problematic, but options include laser, dermabrasion, and surgery.

A patient-level analysis drawn from three randomized, controlled trials finds no evidence that direct stenting improved myocardial reperfusion or clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention.

Patients who underwent thrombus aspiration were more likely to receive direct stenting than conventional stenting, but there was no interaction between thrombus aspiration and outcomes, Karim D. Mahmoud, MD, reported in the European Heart Journal.

Direct stenting – stent implantation without balloon predilatation – has been widely adopted in an effort to improve PCI outcomes in STEMI patients, though no formal guidelines call for it. Small trials have suggested a benefit, but no large, definitive trials have been conducted.

Three previous trials have looked at thrombus aspiration in STEMI patients: TAPAS (the Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study) found that routine manual thrombus aspiration led to better myocardial reperfusion and lower 1-year cardiac mortality (N Engl J Med. 2008 Feb 7;358:557-67). Two larger trials – TASTE (Thrombus Aspiration in ST Elevation Myocardial Infarction in Scandinavia; N Engl J Med. 2013 Oct 24;369[17]:1587-97) and TOTAL (Trial of Routine Aspiration Thrombectomy with PCI vs. PCI Alone in Patients with STEMI; N Engl J Med. 2015 Apr 9;372[15]:1389-98) – both failed to show any benefit of routine thrombus aspiration. As a result, international guidelines recommended use of thrombus aspiration only in selected patients.

The TASTE and TOTAL trials suggested that thrombus aspiration may have led to higher rates of direct stenting, but those rates were lower in TAPAS. Some have suggested that a synergistic effect between thrombus aspiration and DS could explain the positive finding in TAPAS, compared with negative findings in TASTE and TOTAL, said Dr. Mahmoud of Erasmus Medical Center, Rotterdam, the Netherlands.

The researchers tested this idea by pooling patient-level data from the more than 17,000 participants in the three studies, 32% of whom underwent direct stenting. Patients who were randomized to undergo thrombus aspiration were nearly twice as likely to undergo direct stenting (41% vs. 22%, P less than .001). When the researchers 1:1 propensity matched direct stenting versus conventional stenting, 30-day cardiovascular death rates were similar between direct (1.7%) and conventional stenting (1.9%), and there was no interaction between direct stenting and thrombus aspiration. The latter result suggested that there is no synergistic effect. Similar results were found at 1-year follow-up, and with respect to 30-day stroke or transient ischemic attack.

One of the study authors received funding and or honoraria from Bayer, Medtronic, Vascular Solutions, Terumo, Boston Scientific, Abbott Vascular, AstraZeneca, and the Medicines Company.
 

SOURCE: Mahmoud KD et al. Eur Heart J. 2018;39:2472-9.

A patient-level analysis drawn from three randomized, controlled trials finds no evidence that direct stenting improved myocardial reperfusion or clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention.

Patients who underwent thrombus aspiration were more likely to receive direct stenting than conventional stenting, but there was no interaction between thrombus aspiration and outcomes, Karim D. Mahmoud, MD, reported in the European Heart Journal.

Direct stenting – stent implantation without balloon predilatation – has been widely adopted in an effort to improve PCI outcomes in STEMI patients, though no formal guidelines call for it. Small trials have suggested a benefit, but no large, definitive trials have been conducted.

Three previous trials have looked at thrombus aspiration in STEMI patients: TAPAS (the Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study) found that routine manual thrombus aspiration led to better myocardial reperfusion and lower 1-year cardiac mortality (N Engl J Med. 2008 Feb 7;358:557-67). Two larger trials – TASTE (Thrombus Aspiration in ST Elevation Myocardial Infarction in Scandinavia; N Engl J Med. 2013 Oct 24;369[17]:1587-97) and TOTAL (Trial of Routine Aspiration Thrombectomy with PCI vs. PCI Alone in Patients with STEMI; N Engl J Med. 2015 Apr 9;372[15]:1389-98) – both failed to show any benefit of routine thrombus aspiration. As a result, international guidelines recommended use of thrombus aspiration only in selected patients.

The TASTE and TOTAL trials suggested that thrombus aspiration may have led to higher rates of direct stenting, but those rates were lower in TAPAS. Some have suggested that a synergistic effect between thrombus aspiration and DS could explain the positive finding in TAPAS, compared with negative findings in TASTE and TOTAL, said Dr. Mahmoud of Erasmus Medical Center, Rotterdam, the Netherlands.

The researchers tested this idea by pooling patient-level data from the more than 17,000 participants in the three studies, 32% of whom underwent direct stenting. Patients who were randomized to undergo thrombus aspiration were nearly twice as likely to undergo direct stenting (41% vs. 22%, P less than .001). When the researchers 1:1 propensity matched direct stenting versus conventional stenting, 30-day cardiovascular death rates were similar between direct (1.7%) and conventional stenting (1.9%), and there was no interaction between direct stenting and thrombus aspiration. The latter result suggested that there is no synergistic effect. Similar results were found at 1-year follow-up, and with respect to 30-day stroke or transient ischemic attack.

One of the study authors received funding and or honoraria from Bayer, Medtronic, Vascular Solutions, Terumo, Boston Scientific, Abbott Vascular, AstraZeneca, and the Medicines Company.
 

SOURCE: Mahmoud KD et al. Eur Heart J. 2018;39:2472-9.

A patient-level analysis drawn from three randomized, controlled trials finds no evidence that direct stenting improved myocardial reperfusion or clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention.

Patients who underwent thrombus aspiration were more likely to receive direct stenting than conventional stenting, but there was no interaction between thrombus aspiration and outcomes, Karim D. Mahmoud, MD, reported in the European Heart Journal.

Direct stenting – stent implantation without balloon predilatation – has been widely adopted in an effort to improve PCI outcomes in STEMI patients, though no formal guidelines call for it. Small trials have suggested a benefit, but no large, definitive trials have been conducted.

Three previous trials have looked at thrombus aspiration in STEMI patients: TAPAS (the Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study) found that routine manual thrombus aspiration led to better myocardial reperfusion and lower 1-year cardiac mortality (N Engl J Med. 2008 Feb 7;358:557-67). Two larger trials – TASTE (Thrombus Aspiration in ST Elevation Myocardial Infarction in Scandinavia; N Engl J Med. 2013 Oct 24;369[17]:1587-97) and TOTAL (Trial of Routine Aspiration Thrombectomy with PCI vs. PCI Alone in Patients with STEMI; N Engl J Med. 2015 Apr 9;372[15]:1389-98) – both failed to show any benefit of routine thrombus aspiration. As a result, international guidelines recommended use of thrombus aspiration only in selected patients.

The TASTE and TOTAL trials suggested that thrombus aspiration may have led to higher rates of direct stenting, but those rates were lower in TAPAS. Some have suggested that a synergistic effect between thrombus aspiration and DS could explain the positive finding in TAPAS, compared with negative findings in TASTE and TOTAL, said Dr. Mahmoud of Erasmus Medical Center, Rotterdam, the Netherlands.

The researchers tested this idea by pooling patient-level data from the more than 17,000 participants in the three studies, 32% of whom underwent direct stenting. Patients who were randomized to undergo thrombus aspiration were nearly twice as likely to undergo direct stenting (41% vs. 22%, P less than .001). When the researchers 1:1 propensity matched direct stenting versus conventional stenting, 30-day cardiovascular death rates were similar between direct (1.7%) and conventional stenting (1.9%), and there was no interaction between direct stenting and thrombus aspiration. The latter result suggested that there is no synergistic effect. Similar results were found at 1-year follow-up, and with respect to 30-day stroke or transient ischemic attack.

One of the study authors received funding and or honoraria from Bayer, Medtronic, Vascular Solutions, Terumo, Boston Scientific, Abbott Vascular, AstraZeneca, and the Medicines Company.
 

SOURCE: Mahmoud KD et al. Eur Heart J. 2018;39:2472-9.

Neuroimaging may be appropriate only for specific types of patients with recurrent seizures who present at emergency departments because the scans are otherwise unlikely to prompt acute changes in treatment, a new multicenter study suggests.

Spotmatik/Thinkstock

“Going forward, our results should help ED providers determine which patients are more likely to derive benefit from neuroimaging and which patients are not likely to benefit,” lead author Martin Salinsky, MD, of Oregon Health & Science University, Portland, said in an interview. “They can be more selective in ordering scans and reduce the total number obtained.”

As the study authors noted in their report, published July 18 in Epilepsia, “head CT is generally considered a benign procedure. However, overuse is problematic.”

The scans are costly and expose patients to radiation equivalent to 10 chest x-rays, the authors wrote. Scans can complicate care by clogging ED work flow and producing false positives, and patients often seize while undergoing scans, creating even more complications, they added.

“There is very little information in the medical literature that would help guide ED providers in their decision of whether to obtain neuroimaging on a patient who presents with a recurrent seizure,” Dr. Salinsky said. “Without this information, the tendency is to be cautious and obtain scans in more patients.”

For the study, the researchers tracked 822 consecutive ED visits for nonindex – recurrent – epileptic seizures at Oregon Health & Science University and VA Portland Health Care medical centers. (Nonindex seizures accounted for 78% of the total seizures that prompted ED care.)

The study subjects were adults treated for seizure as the main complaint. Patients who had a history of seizures but hadn’t had one for at least 5 years were excluded.

Of the total nonindex seizures, 46% of those resulted in neuroimaging.

“The overall yield of neuroimaging in this patient group was 2%-3%,” Dr. Salinsky said, referring to the percentage of patients whose scans resulted in an acute change in management.

False positives due to imaging artifacts were subsequently discovered in 3 of the 11 patients whose neuroimaging prompted an acute change in management. When the false positives were removed, the yield of acute management changes prompted by neuroimaging decreased to 2.1% overall.

“Three clinical factors – acute head trauma, prolonged alteration of consciousness, and focal neurological examination [at presentation] – were associated with an increased yield of imaging,” he said. “Absent all three factors, the yield in our patients was zero.”

At the two medical centers, the percentages of patients with acute head trauma were 10% and 15%. Prolonged alteration of consciousness occurred in 6% at both centers, and focal neurological examination at presentation was observed in 12% and 14%.

A fourth factor, presentation with status epilepticus/acute repetitive seizures, “bordered on statistical significance and might have reached significance in a larger series,” the authors wrote.

As they put it, “these results support a more conservative use of ED neuroimaging for nonindex seizures, based on clinical factors at the time of presentation. ... without specific indications, ED neuroimaging for nonindex seizures is unlikely to result in an acute change in care.”

The study authors estimated that hundreds of millions of dollars could be saved annually in the United States if neuroimaging in these ED patients could be cut in half.

No study funding was reported, and the authors reported no relevant disclosures.

SOURCE: Salinsky M et al. Epilepsia. 2018 July 18. doi: 10.1111/epi.14518

Neuroimaging may be appropriate only for specific types of patients with recurrent seizures who present at emergency departments because the scans are otherwise unlikely to prompt acute changes in treatment, a new multicenter study suggests.

Spotmatik/Thinkstock

“Going forward, our results should help ED providers determine which patients are more likely to derive benefit from neuroimaging and which patients are not likely to benefit,” lead author Martin Salinsky, MD, of Oregon Health & Science University, Portland, said in an interview. “They can be more selective in ordering scans and reduce the total number obtained.”

As the study authors noted in their report, published July 18 in Epilepsia, “head CT is generally considered a benign procedure. However, overuse is problematic.”

The scans are costly and expose patients to radiation equivalent to 10 chest x-rays, the authors wrote. Scans can complicate care by clogging ED work flow and producing false positives, and patients often seize while undergoing scans, creating even more complications, they added.

“There is very little information in the medical literature that would help guide ED providers in their decision of whether to obtain neuroimaging on a patient who presents with a recurrent seizure,” Dr. Salinsky said. “Without this information, the tendency is to be cautious and obtain scans in more patients.”

For the study, the researchers tracked 822 consecutive ED visits for nonindex – recurrent – epileptic seizures at Oregon Health & Science University and VA Portland Health Care medical centers. (Nonindex seizures accounted for 78% of the total seizures that prompted ED care.)

The study subjects were adults treated for seizure as the main complaint. Patients who had a history of seizures but hadn’t had one for at least 5 years were excluded.

Of the total nonindex seizures, 46% of those resulted in neuroimaging.

“The overall yield of neuroimaging in this patient group was 2%-3%,” Dr. Salinsky said, referring to the percentage of patients whose scans resulted in an acute change in management.

False positives due to imaging artifacts were subsequently discovered in 3 of the 11 patients whose neuroimaging prompted an acute change in management. When the false positives were removed, the yield of acute management changes prompted by neuroimaging decreased to 2.1% overall.

“Three clinical factors – acute head trauma, prolonged alteration of consciousness, and focal neurological examination [at presentation] – were associated with an increased yield of imaging,” he said. “Absent all three factors, the yield in our patients was zero.”

At the two medical centers, the percentages of patients with acute head trauma were 10% and 15%. Prolonged alteration of consciousness occurred in 6% at both centers, and focal neurological examination at presentation was observed in 12% and 14%.

A fourth factor, presentation with status epilepticus/acute repetitive seizures, “bordered on statistical significance and might have reached significance in a larger series,” the authors wrote.

As they put it, “these results support a more conservative use of ED neuroimaging for nonindex seizures, based on clinical factors at the time of presentation. ... without specific indications, ED neuroimaging for nonindex seizures is unlikely to result in an acute change in care.”

The study authors estimated that hundreds of millions of dollars could be saved annually in the United States if neuroimaging in these ED patients could be cut in half.

No study funding was reported, and the authors reported no relevant disclosures.

SOURCE: Salinsky M et al. Epilepsia. 2018 July 18. doi: 10.1111/epi.14518

Neuroimaging may be appropriate only for specific types of patients with recurrent seizures who present at emergency departments because the scans are otherwise unlikely to prompt acute changes in treatment, a new multicenter study suggests.

Spotmatik/Thinkstock

“Going forward, our results should help ED providers determine which patients are more likely to derive benefit from neuroimaging and which patients are not likely to benefit,” lead author Martin Salinsky, MD, of Oregon Health & Science University, Portland, said in an interview. “They can be more selective in ordering scans and reduce the total number obtained.”

As the study authors noted in their report, published July 18 in Epilepsia, “head CT is generally considered a benign procedure. However, overuse is problematic.”

The scans are costly and expose patients to radiation equivalent to 10 chest x-rays, the authors wrote. Scans can complicate care by clogging ED work flow and producing false positives, and patients often seize while undergoing scans, creating even more complications, they added.

“There is very little information in the medical literature that would help guide ED providers in their decision of whether to obtain neuroimaging on a patient who presents with a recurrent seizure,” Dr. Salinsky said. “Without this information, the tendency is to be cautious and obtain scans in more patients.”

For the study, the researchers tracked 822 consecutive ED visits for nonindex – recurrent – epileptic seizures at Oregon Health & Science University and VA Portland Health Care medical centers. (Nonindex seizures accounted for 78% of the total seizures that prompted ED care.)

The study subjects were adults treated for seizure as the main complaint. Patients who had a history of seizures but hadn’t had one for at least 5 years were excluded.

Of the total nonindex seizures, 46% of those resulted in neuroimaging.

“The overall yield of neuroimaging in this patient group was 2%-3%,” Dr. Salinsky said, referring to the percentage of patients whose scans resulted in an acute change in management.

False positives due to imaging artifacts were subsequently discovered in 3 of the 11 patients whose neuroimaging prompted an acute change in management. When the false positives were removed, the yield of acute management changes prompted by neuroimaging decreased to 2.1% overall.

“Three clinical factors – acute head trauma, prolonged alteration of consciousness, and focal neurological examination [at presentation] – were associated with an increased yield of imaging,” he said. “Absent all three factors, the yield in our patients was zero.”

At the two medical centers, the percentages of patients with acute head trauma were 10% and 15%. Prolonged alteration of consciousness occurred in 6% at both centers, and focal neurological examination at presentation was observed in 12% and 14%.

A fourth factor, presentation with status epilepticus/acute repetitive seizures, “bordered on statistical significance and might have reached significance in a larger series,” the authors wrote.

As they put it, “these results support a more conservative use of ED neuroimaging for nonindex seizures, based on clinical factors at the time of presentation. ... without specific indications, ED neuroimaging for nonindex seizures is unlikely to result in an acute change in care.”

The study authors estimated that hundreds of millions of dollars could be saved annually in the United States if neuroimaging in these ED patients could be cut in half.

No study funding was reported, and the authors reported no relevant disclosures.

SOURCE: Salinsky M et al. Epilepsia. 2018 July 18. doi: 10.1111/epi.14518

NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

mzoler@mdedge.com

Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

mzoler@mdedge.com

Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

mzoler@mdedge.com

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

mdales@mdedge.com

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

mdales@mdedge.com

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

mdales@mdedge.com