Conference Coverage

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

For patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL), adding avadomide to standard therapy may reduce the likelihood of treatment failure, based on phase 1 results.

The regimen was well tolerated and had a complete response rate of 79%, reported lead author Neha Mehta-Shah, MD, of Washington University, St. Louis, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

Newly diagnosed DLBCL “remains a clinical challenge,” Dr. Mehta-Shah said, noting a treatment failure rate of 30%-50% for standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP-21), and worse outcomes among patients with high-risk disease.

In an effort to boost efficacy, the investigators turned to avadomide, a cereblon E3 ligase modulator, which previously demonstrated a complete response rate of 11% when used as monotherapy for patients with relapsed or refractory DLBCL.

The present phase 1 data included 35 adults with newly diagnosed DLBCL who had measurable lesions of at least 2.0 cm and International Prognostic Indices (IPI) between 3-5. Specifically, 51% of patients had an IPI of 3, while 49% had an IPI of 4-5.

All patients received standard R-CHOP with pegfilgrastim (to stimulate white blood cell growth), plus escalating doses of oral avadomide from 1-3 mg. Treatment was delivered, when tolerated, for up to six 21-day cycles. Depending on dose level, avadomide was given during either 2 or 3 out of 3 weeks. During treatment weeks, avadomide was given on 5 of 7 days.

The primary objectives were safety, tolerability, and complete response rate. Secondary objectives included biomarkers and additional efficacy measures, while exploratory analyses were also conducted to assess pharmacokinetics and pharmacodynamics.

Out of 34 patients evaluable for efficacy, the complete response rate was 79% and the objective response rate was 88%. After a median follow-up of 10 months, the 1-year progression-free survival rate was 80%.

“The combination showed promising efficacy,” Dr. Mehta-Shah said.

The regimen was also well tolerated and demonstrated an “acceptable safety profile consistent with either therapy alone,” Dr. Mehta-Shah added.

Most patients (91%) completed all six cycles of therapy. Median relative total dose intensities were 99% and 95% for avadomide and R-CHOP-21, respectively. Approximately two out of three patients (66%) required dose interruptions of avadomide, and 9% required dose reductions because of adverse events.

Dose-limiting toxicities occurred in six patients, including sepsis, febrile neutropenia caused by skin infections, febrile neutropenia with hypotension, febrile neutropenia, pneumonia, and neutropenia with bacterial hepatic infection. Based on these findings, the recommended phase 2 dose of avadomide was determined to be 3 mg given during 2 out of 3 weeks.

About 74% of patients had grade 3-4 treatment-emergent adverse events, the most common of which were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and febrile neutropenia (11%).

During the second cycle of therapy, one patient died because of concurrent pneumonia. After completion of therapy, two patients developed cardiac failure, and data gathered after each cycle showed that five patients had developed elevated levels of troponin or brain natriuretic peptide.

Flow cytometry showed that avadomide had proimmunomodulatory effects, including expansion of memory T-cell populations and enhanced proliferation of T cells and NK cells. The magnitude of this latter increase was greater than that observed in previous studies involving R-CHOP and durvalumab, Dr. Mehta-Shah noted.

“We look forward to following up on this data regarding the progression-free survival over a longer period of time,” Dr. Mehta-Shah said. “The results of this trial indicate that further evaluation of cereblon-modulating compounds combined with immunochemotherapy for patients with previously untreated diffuse large B-cell lymphoma is worthy of further exploration.”

Invited discussant Edward Yeh, MD, of the University of Missouri–Columbia, called cereblon modulators such as avadomide and thalidomide a “very exciting class of anticancer therapy.”

In a virtual presentation, Dr. Yeh noted that cereblon modulators have several advantages, including “good absorption, distribution, metabolism, [and] elimination,” plus relatively low susceptibility to mutation-directed drug resistance.

Despite some drawbacks, including difficulty to design and synthesize, Dr. Yeh suggested that this drug class may play a bigger role over time.

“We’re expecting more cancer therapy to come to fruition through the utilization of this posttranslational, protein-modification pathway,” he concluded.

The study was funded by Celgene. The investigators disclosed additional relationships with Kyowa Hakko Kirin, AstraZeneca, Roche, and others.

SOURCE: Mehta-Shah N et al. ASCO 2020, Abstract 3501.

For patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL), adding avadomide to standard therapy may reduce the likelihood of treatment failure, based on phase 1 results.

The regimen was well tolerated and had a complete response rate of 79%, reported lead author Neha Mehta-Shah, MD, of Washington University, St. Louis, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

Newly diagnosed DLBCL “remains a clinical challenge,” Dr. Mehta-Shah said, noting a treatment failure rate of 30%-50% for standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP-21), and worse outcomes among patients with high-risk disease.

In an effort to boost efficacy, the investigators turned to avadomide, a cereblon E3 ligase modulator, which previously demonstrated a complete response rate of 11% when used as monotherapy for patients with relapsed or refractory DLBCL.

The present phase 1 data included 35 adults with newly diagnosed DLBCL who had measurable lesions of at least 2.0 cm and International Prognostic Indices (IPI) between 3-5. Specifically, 51% of patients had an IPI of 3, while 49% had an IPI of 4-5.

All patients received standard R-CHOP with pegfilgrastim (to stimulate white blood cell growth), plus escalating doses of oral avadomide from 1-3 mg. Treatment was delivered, when tolerated, for up to six 21-day cycles. Depending on dose level, avadomide was given during either 2 or 3 out of 3 weeks. During treatment weeks, avadomide was given on 5 of 7 days.

The primary objectives were safety, tolerability, and complete response rate. Secondary objectives included biomarkers and additional efficacy measures, while exploratory analyses were also conducted to assess pharmacokinetics and pharmacodynamics.

Out of 34 patients evaluable for efficacy, the complete response rate was 79% and the objective response rate was 88%. After a median follow-up of 10 months, the 1-year progression-free survival rate was 80%.

“The combination showed promising efficacy,” Dr. Mehta-Shah said.

The regimen was also well tolerated and demonstrated an “acceptable safety profile consistent with either therapy alone,” Dr. Mehta-Shah added.

Most patients (91%) completed all six cycles of therapy. Median relative total dose intensities were 99% and 95% for avadomide and R-CHOP-21, respectively. Approximately two out of three patients (66%) required dose interruptions of avadomide, and 9% required dose reductions because of adverse events.

Dose-limiting toxicities occurred in six patients, including sepsis, febrile neutropenia caused by skin infections, febrile neutropenia with hypotension, febrile neutropenia, pneumonia, and neutropenia with bacterial hepatic infection. Based on these findings, the recommended phase 2 dose of avadomide was determined to be 3 mg given during 2 out of 3 weeks.

About 74% of patients had grade 3-4 treatment-emergent adverse events, the most common of which were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and febrile neutropenia (11%).

During the second cycle of therapy, one patient died because of concurrent pneumonia. After completion of therapy, two patients developed cardiac failure, and data gathered after each cycle showed that five patients had developed elevated levels of troponin or brain natriuretic peptide.

Flow cytometry showed that avadomide had proimmunomodulatory effects, including expansion of memory T-cell populations and enhanced proliferation of T cells and NK cells. The magnitude of this latter increase was greater than that observed in previous studies involving R-CHOP and durvalumab, Dr. Mehta-Shah noted.

“We look forward to following up on this data regarding the progression-free survival over a longer period of time,” Dr. Mehta-Shah said. “The results of this trial indicate that further evaluation of cereblon-modulating compounds combined with immunochemotherapy for patients with previously untreated diffuse large B-cell lymphoma is worthy of further exploration.”

Invited discussant Edward Yeh, MD, of the University of Missouri–Columbia, called cereblon modulators such as avadomide and thalidomide a “very exciting class of anticancer therapy.”

In a virtual presentation, Dr. Yeh noted that cereblon modulators have several advantages, including “good absorption, distribution, metabolism, [and] elimination,” plus relatively low susceptibility to mutation-directed drug resistance.

Despite some drawbacks, including difficulty to design and synthesize, Dr. Yeh suggested that this drug class may play a bigger role over time.

“We’re expecting more cancer therapy to come to fruition through the utilization of this posttranslational, protein-modification pathway,” he concluded.

The study was funded by Celgene. The investigators disclosed additional relationships with Kyowa Hakko Kirin, AstraZeneca, Roche, and others.

SOURCE: Mehta-Shah N et al. ASCO 2020, Abstract 3501.

For patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL), adding avadomide to standard therapy may reduce the likelihood of treatment failure, based on phase 1 results.

The regimen was well tolerated and had a complete response rate of 79%, reported lead author Neha Mehta-Shah, MD, of Washington University, St. Louis, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

Newly diagnosed DLBCL “remains a clinical challenge,” Dr. Mehta-Shah said, noting a treatment failure rate of 30%-50% for standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP-21), and worse outcomes among patients with high-risk disease.

In an effort to boost efficacy, the investigators turned to avadomide, a cereblon E3 ligase modulator, which previously demonstrated a complete response rate of 11% when used as monotherapy for patients with relapsed or refractory DLBCL.

The present phase 1 data included 35 adults with newly diagnosed DLBCL who had measurable lesions of at least 2.0 cm and International Prognostic Indices (IPI) between 3-5. Specifically, 51% of patients had an IPI of 3, while 49% had an IPI of 4-5.

All patients received standard R-CHOP with pegfilgrastim (to stimulate white blood cell growth), plus escalating doses of oral avadomide from 1-3 mg. Treatment was delivered, when tolerated, for up to six 21-day cycles. Depending on dose level, avadomide was given during either 2 or 3 out of 3 weeks. During treatment weeks, avadomide was given on 5 of 7 days.

The primary objectives were safety, tolerability, and complete response rate. Secondary objectives included biomarkers and additional efficacy measures, while exploratory analyses were also conducted to assess pharmacokinetics and pharmacodynamics.

Out of 34 patients evaluable for efficacy, the complete response rate was 79% and the objective response rate was 88%. After a median follow-up of 10 months, the 1-year progression-free survival rate was 80%.

“The combination showed promising efficacy,” Dr. Mehta-Shah said.

The regimen was also well tolerated and demonstrated an “acceptable safety profile consistent with either therapy alone,” Dr. Mehta-Shah added.

Most patients (91%) completed all six cycles of therapy. Median relative total dose intensities were 99% and 95% for avadomide and R-CHOP-21, respectively. Approximately two out of three patients (66%) required dose interruptions of avadomide, and 9% required dose reductions because of adverse events.

Dose-limiting toxicities occurred in six patients, including sepsis, febrile neutropenia caused by skin infections, febrile neutropenia with hypotension, febrile neutropenia, pneumonia, and neutropenia with bacterial hepatic infection. Based on these findings, the recommended phase 2 dose of avadomide was determined to be 3 mg given during 2 out of 3 weeks.

About 74% of patients had grade 3-4 treatment-emergent adverse events, the most common of which were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and febrile neutropenia (11%).

During the second cycle of therapy, one patient died because of concurrent pneumonia. After completion of therapy, two patients developed cardiac failure, and data gathered after each cycle showed that five patients had developed elevated levels of troponin or brain natriuretic peptide.

Flow cytometry showed that avadomide had proimmunomodulatory effects, including expansion of memory T-cell populations and enhanced proliferation of T cells and NK cells. The magnitude of this latter increase was greater than that observed in previous studies involving R-CHOP and durvalumab, Dr. Mehta-Shah noted.

“We look forward to following up on this data regarding the progression-free survival over a longer period of time,” Dr. Mehta-Shah said. “The results of this trial indicate that further evaluation of cereblon-modulating compounds combined with immunochemotherapy for patients with previously untreated diffuse large B-cell lymphoma is worthy of further exploration.”

Invited discussant Edward Yeh, MD, of the University of Missouri–Columbia, called cereblon modulators such as avadomide and thalidomide a “very exciting class of anticancer therapy.”

In a virtual presentation, Dr. Yeh noted that cereblon modulators have several advantages, including “good absorption, distribution, metabolism, [and] elimination,” plus relatively low susceptibility to mutation-directed drug resistance.

Despite some drawbacks, including difficulty to design and synthesize, Dr. Yeh suggested that this drug class may play a bigger role over time.

“We’re expecting more cancer therapy to come to fruition through the utilization of this posttranslational, protein-modification pathway,” he concluded.

The study was funded by Celgene. The investigators disclosed additional relationships with Kyowa Hakko Kirin, AstraZeneca, Roche, and others.

SOURCE: Mehta-Shah N et al. ASCO 2020, Abstract 3501.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Adding the immune checkpoint inhibitor pembrolizumab to chemotherapy resulted in a modest improvement in progression-free survival (PFS) but no overall survival (OS) benefit as first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), results of the KEYNOTE-604 study showed.

Among 453 patients with ES-SCLC randomized to receive pembrolizumab plus etoposide and a platinum agent (EP) or placebo, the median PFS was 4.5 months with pembrolizumab and with 4.3 months with placebo.

This difference, although small, met the prespecified definition for significance, with a hazard ratio favoring pembrolizumab of 0.75 (P = .0023), reported Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Median OS, the other primary endpoint, was 10.8 months for patients who received pembrolizumab and 9.7 months for those who received placebo. Although this translated to a hazard ratio of 0.80 for pembrolizumab, the P value of .0164 missed the prespecified threshold of .0128 and was therefore not statistically significant.

Dr. Rudin presented these results as part of the American Society of Clinical Oncology virtual scientific program. The study was also published online to coincide with the abstract’s release in the Journal of Clinical Oncology.
 

Beneficial but not practice-changing (yet)

“The addition of pembrolizumab results in durable responses in a subset of patients,” Dr. Rudin said. “I believe additional correlative analyses may help to identify those patients who derive long-term benefit from pembrolizumab.

“The safety profile was manageable with no new or unexpected toxicities. Taken together, these data support the benefit of pembrolizumab in patients with small cell lung cancer and add to the growing body of evidence supporting the value of immune checkpoint inhibitors in a historically difficult-to-treat cancer.”

The results suggest combination pembrolizumab and chemotherapy offers a “viable platform for a novel treatment strategy,” said invited discussant Taofeek K. Owonikoko, MD, PhD, director of thoracic oncology at the Winship Cancer Institute of Emory University in Atlanta.

However, because the trial did not meet the predefined threshold for success, “the immediate impact on practice of this trial is limited at present, and any future impact will have to be supported by regulatory decision,” Dr. Owonikoko said.

“The outcome of this trial also highlights the need for an uncomplicated study design and straightforward analytical plan to ensure accurate results,” he added.
 

Study details

KEYNOTE-604 investigators enrolled 453 patients with ES-SCLC who had no prior systemic therapy, good performance status, and a life expectancy of at least 3 months. Patients were stratified by type of platinum agent (cisplatin vs. carboplatin), Eastern Cooperative Oncology Group performance status 0 or 1, and lactate dehydrogenase levels below or above the upper limit of normal.

Patients were randomized to receive pembrolizumab at 200 mg or normal saline placebo on day 1. Both arms also received etoposide at 100 mg/m² on days 1-3 and investigator’s choice of carboplatin to an area under the curve of 5 on day 1 or cisplatin at 75 mg/m² on day 1 for four cycles every 3 weeks.

The assigned agent (pembrolizumab or placebo) could then be continued as maintenance therapy for up to 31 cycles every 21 days.

Patients with a complete or partial response after cycle 4 could receive up to 25 Gy of prophylactic cranial irradiation delivered over 10 fractions at the investigator’s discretion.
 

Survival and response

As noted, the median PFS was modestly but significantly longer with pembrolizumab plus EP at the second interim analysis, the protocol-specified time for final PFS analysis. The estimated 12-months PFS rates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.

The final analysis was planned to occur about 31 months after the start of the study or when 284 deaths had occurred, whichever was later. At the final analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm. The hazard ratio was 0.73 (95% confidence interval 0.60-0.88).

The 12-month OS rate was 45.1% in the pembrolizumab arm and 39.6% in the placebo arm. Respective 24-month OS rates were 22.5% and 11.2%.

Overall responses rates were 70.6% in the pembrolizumab arm and 61.8% in the placebo arm. There were four and two complete responses per arm, respectively.
 

Safety

Approximately 75% of patients in both arms experienced grade 3 or 4 adverse events.

Fatal adverse events occurred in 6.3% of patients in the pembrolizumab arm and 5.4% in the control arm. The rates of death attributed to study treatment were identical, at 2.7% in each arm.

Events leading to discontinuation occurred in 14.8% of patients who received pembrolizumab and 6.3% of patients who received placebo. Adverse events leading to all treatment discontinuation were similar, at 4% and 3.6%, respectively.

The most common adverse events were hematologic, which are common with EP chemotherapy and did not appear to be exacerbated by the addition of pembrolizumab. Aside from hematologic toxicities, most events were of grade 1 or 2 severity.

Immune-mediated adverse events of any kind occurred in 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Grade 3 or 4 immune-mediated events occurred in 7.2% and 1.3%, respectively.

There were no deaths from immune-mediated reactions in the pembrolizumab arm, but one patient on placebo died from pneumonia.

Merck Sharp & Dohme supported the study. Dr. Rudin disclosed institutional research funding from Merck and a consulting or advisory role for other companies. Dr. Owonikoko disclosed a consulting/advisory role and institutional research funding from Merck and others, and he is a cofounder and stock owner in Cambium Oncology.

SOURCE: Rudin CM et al. ASCO 2020. Abstract 9001.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Reports of herpes zoster virus (HZV) among patients being treated with disease-modifying therapies (DMTs) for multiple sclerosis (MS) are nearly five times higher among women versus men and commonly occur in people under the age of 40, a new study of adverse event reports on a variety of DMTs suggests.

DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.

“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.

For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.

They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.

Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.

Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.

Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.

“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.

Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.

In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.

“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”

The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”

While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.

“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.

“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”

He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.

“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”

Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.

This article first appeared on Medscape.com.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

Among patients with ankylosing spondylitis or undifferentiated spondyloarthritis, risk for anterior uveitis may hinge on the choice of biologic disease-modifying antirheumatic drug (bDMARD), a large Swedish cohort study suggests.

Study results were reported in the opening plenary abstract session at the annual European Congress of Rheumatology, held online this year due to COVID-19.

“Randomized, controlled trials indicate that compared to tumor necrosis factor (TNF) inhibitors, secukinumab has similar efficacy regarding axial inflammation in spondyloarthritis and better efficacy regarding cutaneous psoriasis, but is inferior in inflammatory bowel disease,” noted lead investigator Ulf Lindström, MD, PhD, of the department of rheumatology and inflammation research in the Institute of Medicine at the University of Gothenburg (Sweden). “However, the efficacy of secukinumab, compared to TNF inhibitors, in anterior uveitis has not been extensively studied.”

The investigators used national registry data to study 3,568 patients with ankylosing spondylitis or undifferentiated spondyloarthritis who started bDMARDs in 2005-2018. They considered four agents: the anti–interleukin-17A antibody secukinumab (Cosentyx) and the TNF inhibitors etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade).

Analyses based on 4,523 treatment episodes showed that after excluding the 23% of patients who had previously experienced anterior uveitis, merely 0.9% of patients experienced new-onset anterior uveitis while on their bDMARD, Dr. Lindström reported.

There was confounding by indication, whereby patients with previous anterior uveitis were channeled toward adalimumab and infliximab, and away from secukinumab and etanercept. In addition, there was confounding by line of treatment, with secukinumab usually used in the third line.

After excluding patients who had experienced anterior uveitis in the past year to partly address confounding, the adjusted risk for first on-treatment anterior uveitis was about twice as high with secukinumab and with etanercept as compared with adalimumab. After additionally excluding all biologic treatment episodes beyond the third line, elevation of risk remained significant only for etanercept.

“There is probably a higher occurrence of anterior uveitis on treatment with secukinumab, compared to adalimumab, but there may still be residual confounding and bias that we need to consider,” Dr. Lindström concluded. “As seen previously, there is a higher occurrence of anterior uveitis on etanercept compared to adalimumab or infliximab.”

Findings in context

“These results are not surprising as we have known that secukinumab and etanercept are not good for controlling recurrent and chronic uveitis,” Nigil Haroon MD, PhD, DM, commented in an interview. However, “a single episode of uveitis or infrequent episodes are not usually considered a contraindication to starting these drugs.”

Study caveats included lack of adjustment for uveitis severity and potentially missed uveitis episodes in patients who treated it themselves with steroid eyedrops, he said. “Standard practice is to keep drops with them to start at the earliest possible time point.”

“It would be useful to know the number of patients who stopped medications as a result of uveitis,” added Dr. Haroon, who is codirector of the spondylitis program at the University Health Network and associate professor of medicine and rheumatology at the University of Toronto. “Time-to-event analysis may also be interesting.”

“The study raises an important point regarding channeling bias, and this is important to consider when interpreting clinical trial data as well. Investigators are unlikely to include patients with history of uveitis (or strong family history of inflammatory bowel disease or personal history of gut symptoms) in studies with IL-17 inhibitors and etanercept. Hence, the results have to be interpreted with caution.”
 

Study details

Dr. Lindström and coinvestigators assessed incidences of any anterior uveitis (ascertained from outpatient ophthalmology visits having this diagnostic code) and of anterior uveitis flares (the subset occurring after a gap of at least 90 days without the diagnosis).

When they excluded patients who had experienced anterior uveitis in the year before starting therapy, secukinumab and etanercept carried the highest incidences of anterior uveitis (6.8 and 7.5 per 100 patient-years, respectively) and anterior uveitis flares (2.8 per 100 patient-years for each), he reported.

With adalimumab as the comparator, adjusted risk for first on-treatment anterior uveitis in this population was significantly higher with secukinumab (hazard ratio, 2.23) and etanercept (hazard ratio, 1.80).

When the investigators additionally excluded episodes of therapy beyond the third line, only etanercept carried notably higher incidences of anterior uveitis (7.0 per 100 patient-years) and anterior uveitis flares (2.6 per 100 patient-years). “This could imply that some of the higher incidence rate seen for secukinumab could be due to the fact that these patients are harder to treat and have received more biologics before,” Dr. Lindström proposed.

With adalimumab again as the comparator, the adjusted risk for first on-treatment anterior uveitis in this population was significantly higher only with etanercept (hazard ratio, 1.85).

A final analysis included all patients who started adalimumab in 2004-2018 and then switched to one of the other agents, dramatically reducing confounding by indication. In this population, the incidence rate ratio of anterior uveitis flares was 3.05 for secukinumab, 1.79 for etanercept, and 0.53 for infliximab, compared with adalimumab.

Dr. Lindström disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding. Dr. Haroon disclosed consulting for Amgen, Abbvie, Eli Lilly, Janssen, Novartis, and UCB.

SOURCE: Lindström U et al. Ann Rheum Dis. 2020;79[suppl 1]:9, Abstract OP0014.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.