Heidi Splete

“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.

She shared her insights on four questions most often asked by patients in her practice:

How long do I need to take this medication?

When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”

Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.

For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.

Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.

In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
 

What should I know about infusion side effects?

Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.

To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.

“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.

AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.

A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.

Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
 

When will I need another dual x-ray absorptiometry scan?

Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.

Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.

Will I need a new medication if I fracture while on treatment?

For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.

It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.

Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.

Global Academy for Medical Education and this news organization are owned by the same parent company.

“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.

She shared her insights on four questions most often asked by patients in her practice:

How long do I need to take this medication?

When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”

Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.

For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.

Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.

In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
 

What should I know about infusion side effects?

Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.

To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.

“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.

AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.

A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.

Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
 

When will I need another dual x-ray absorptiometry scan?

Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.

Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.

Will I need a new medication if I fracture while on treatment?

For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.

It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.

Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.

Global Academy for Medical Education and this news organization are owned by the same parent company.

“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.

She shared her insights on four questions most often asked by patients in her practice:

How long do I need to take this medication?

When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”

Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.

For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.

Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.

In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
 

What should I know about infusion side effects?

Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.

To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.

“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.

AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.

A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.

Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
 

When will I need another dual x-ray absorptiometry scan?

Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.

Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.

Will I need a new medication if I fracture while on treatment?

For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.

It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.

Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

When it comes to preventing infection in rheumatology patients, “vaccination is the best mode of infection protection” and works synergistically with masks and hand washing, according to Leonard H. Calabrese, DO.

“Patients with rheumatic diseases have increased morbidity and mortality [from infection] and a lot of risk factors, including age, comorbidities, cytopenias, and extra-articular disease immunosuppression,” he said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Unfortunately, vaccination uptake remains “much lower than we would like in this country,” he said. Notably, influenza vaccination remains well below the World Health Organization target of 75%, he said.
 

Influenza vaccination

Flu vaccination will be even more important this year in the context of the COVID-19 pandemic, said Dr. Calabrese, professor of medicine and the RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic in Ohio. “For everyone who comes in with a respiratory illness, we will have to figure out whether it is flu or COVID,” he emphasized.

The Centers for Disease Control and Prevention recommendations include a detailed special considerations section for patients with immunocompromising conditions; “the notes have everything you need to know” about advising rheumatology patients, most of whom can safely receive a flu vaccine, he said.

One concern that always comes up is whether an antibody response will be suppressed based on therapy, Dr. Calabrese noted. Two major drugs with the greatest ability to reduce response are methotrexate and rituximab, he said. His tip: “Withhold methotrexate for two doses following seasonal flu vaccination.” This advice stems from a series of “practice-changing” studies by Park et al. published in 2017, 2018, and 2019 that showed benefit in withholding methotrexate for two doses following vaccination.

In the past, high-dose trivalent flu vaccines have been more expensive, and not necessarily practice changing, with studies showing varying clinical effectiveness and cost-effectiveness, Dr. Calabrese said. This year, a high-dose quadrivalent vaccine should be available that showed a 24% improvement in protection from all strains of influenza, compared with the standard vaccine in a head-to-head, randomized, controlled trial, he noted.

“All patients in rheumatology practices should get a flu vaccine,” with a 2-week hold on methotrexate following vaccination, he advised, and those aged 65 years and older should receive the high-dose quadrivalent. Younger patients on immunosuppressive therapy also might be considered for the high-dose vaccine, he said.

Pneumococcal vaccination

Dr. Calabrese also emphasized the value of pneumococcal vaccines for rheumatology patients. “The mortality for invasive disease ranges from 5% to 32%, but patients with immunocompromising conditions are at increased risk.”

Dr. Calabrese added a note on safety: Patients with cryopyrin-associated periodic syndrome (CAPS), a rare hereditary inflammatory disorder with cutaneous, neurologic, ophthalmologic, and rheumatologic manifestations, may have severe local and systemic reactions to the 23-valent polysaccharide vaccine (PPSV23), he said.

However, immunization against pneumococcal disease is safe and effective for most patients with autoimmune and inflammatory disorders regardless of their current therapy, he said. As with influenza, the CDC’s vaccination recommendations provide details for special situations, including immunocompromised individuals, he noted.

Dr. Calabrese recommended the 13-valent pneumococcal conjugate vaccine (PCV13) as soon as possible for rheumatology patients who have never been vaccinated, with follow-up doses of the 23-valent polysaccharide vaccine (PPSV23) at least 8 weeks later, and a PPSV23 booster 5 years after the first PPSV23 dose.
 

Protecting against shingles

When it comes to managing the varicella zoster virus (VZV) in immunocompromised patients, “prevention is preferable to treatment, as our patients are particularly vulnerable because of age and declining immunity,” Dr. Calabrese said.

Prevention is important because “once herpes zoster develops, the available treatments, including antiviral therapy, do not prevent postherpetic neuralgia in all patients,” he emphasized. “The treatments are complicated and not always effective,” he added.

The complications of zoster are well known, but recent data show an increased risk of cardiovascular disease as well, Dr. Calabrese said. “All the more reason to protect rheumatology patients from incident zoster,” he said.

Currently, the nonlive recombinant subunit zoster vaccine (Shingrix) is the preferred option for VZV vaccination according to the CDC’s Advisory Committee on Immunization Practices, Dr. Calabrese said. The CDC initially recommended its use to prevent herpes zoster and related complications in all immunocompetent adults aged 50 years and older; in an update, a C-level recommendation extends to “all patients aged 50 with or without immunosuppressive illnesses regardless of previous Zostavax exposure,” Dr. Calabrese said. “All patients on or starting [Janus] kinase inhibitors, regardless of age, should be considered” to receive the herpes zoster vaccine, he noted.

In general, promoting vaccination for rheumatology patients and for all patients is a multipronged effort that might include reminders, rewards, education, and standing orders, Dr. Calabrese said. Clinicians must continue to educate patients not only by strongly recommending the appropriate vaccines, but dispelling myths about vaccination, addressing fears, and providing current and accurate information, he said.

Dr. Calabrese disclosed relationships with AbbVie, Bristol-Myers Squibb, Crescendo, Genentech, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sanofi-Regeneron, and UCB.

Global Academy for Medical Education and this news organization are owned by the same parent company.

When it comes to preventing infection in rheumatology patients, “vaccination is the best mode of infection protection” and works synergistically with masks and hand washing, according to Leonard H. Calabrese, DO.

“Patients with rheumatic diseases have increased morbidity and mortality [from infection] and a lot of risk factors, including age, comorbidities, cytopenias, and extra-articular disease immunosuppression,” he said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Unfortunately, vaccination uptake remains “much lower than we would like in this country,” he said. Notably, influenza vaccination remains well below the World Health Organization target of 75%, he said.
 

Influenza vaccination

Flu vaccination will be even more important this year in the context of the COVID-19 pandemic, said Dr. Calabrese, professor of medicine and the RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic in Ohio. “For everyone who comes in with a respiratory illness, we will have to figure out whether it is flu or COVID,” he emphasized.

The Centers for Disease Control and Prevention recommendations include a detailed special considerations section for patients with immunocompromising conditions; “the notes have everything you need to know” about advising rheumatology patients, most of whom can safely receive a flu vaccine, he said.

One concern that always comes up is whether an antibody response will be suppressed based on therapy, Dr. Calabrese noted. Two major drugs with the greatest ability to reduce response are methotrexate and rituximab, he said. His tip: “Withhold methotrexate for two doses following seasonal flu vaccination.” This advice stems from a series of “practice-changing” studies by Park et al. published in 2017, 2018, and 2019 that showed benefit in withholding methotrexate for two doses following vaccination.

In the past, high-dose trivalent flu vaccines have been more expensive, and not necessarily practice changing, with studies showing varying clinical effectiveness and cost-effectiveness, Dr. Calabrese said. This year, a high-dose quadrivalent vaccine should be available that showed a 24% improvement in protection from all strains of influenza, compared with the standard vaccine in a head-to-head, randomized, controlled trial, he noted.

“All patients in rheumatology practices should get a flu vaccine,” with a 2-week hold on methotrexate following vaccination, he advised, and those aged 65 years and older should receive the high-dose quadrivalent. Younger patients on immunosuppressive therapy also might be considered for the high-dose vaccine, he said.

Pneumococcal vaccination

Dr. Calabrese also emphasized the value of pneumococcal vaccines for rheumatology patients. “The mortality for invasive disease ranges from 5% to 32%, but patients with immunocompromising conditions are at increased risk.”

Dr. Calabrese added a note on safety: Patients with cryopyrin-associated periodic syndrome (CAPS), a rare hereditary inflammatory disorder with cutaneous, neurologic, ophthalmologic, and rheumatologic manifestations, may have severe local and systemic reactions to the 23-valent polysaccharide vaccine (PPSV23), he said.

However, immunization against pneumococcal disease is safe and effective for most patients with autoimmune and inflammatory disorders regardless of their current therapy, he said. As with influenza, the CDC’s vaccination recommendations provide details for special situations, including immunocompromised individuals, he noted.

Dr. Calabrese recommended the 13-valent pneumococcal conjugate vaccine (PCV13) as soon as possible for rheumatology patients who have never been vaccinated, with follow-up doses of the 23-valent polysaccharide vaccine (PPSV23) at least 8 weeks later, and a PPSV23 booster 5 years after the first PPSV23 dose.
 

Protecting against shingles

When it comes to managing the varicella zoster virus (VZV) in immunocompromised patients, “prevention is preferable to treatment, as our patients are particularly vulnerable because of age and declining immunity,” Dr. Calabrese said.

Prevention is important because “once herpes zoster develops, the available treatments, including antiviral therapy, do not prevent postherpetic neuralgia in all patients,” he emphasized. “The treatments are complicated and not always effective,” he added.

The complications of zoster are well known, but recent data show an increased risk of cardiovascular disease as well, Dr. Calabrese said. “All the more reason to protect rheumatology patients from incident zoster,” he said.

Currently, the nonlive recombinant subunit zoster vaccine (Shingrix) is the preferred option for VZV vaccination according to the CDC’s Advisory Committee on Immunization Practices, Dr. Calabrese said. The CDC initially recommended its use to prevent herpes zoster and related complications in all immunocompetent adults aged 50 years and older; in an update, a C-level recommendation extends to “all patients aged 50 with or without immunosuppressive illnesses regardless of previous Zostavax exposure,” Dr. Calabrese said. “All patients on or starting [Janus] kinase inhibitors, regardless of age, should be considered” to receive the herpes zoster vaccine, he noted.

In general, promoting vaccination for rheumatology patients and for all patients is a multipronged effort that might include reminders, rewards, education, and standing orders, Dr. Calabrese said. Clinicians must continue to educate patients not only by strongly recommending the appropriate vaccines, but dispelling myths about vaccination, addressing fears, and providing current and accurate information, he said.

Dr. Calabrese disclosed relationships with AbbVie, Bristol-Myers Squibb, Crescendo, Genentech, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sanofi-Regeneron, and UCB.

Global Academy for Medical Education and this news organization are owned by the same parent company.

When it comes to preventing infection in rheumatology patients, “vaccination is the best mode of infection protection” and works synergistically with masks and hand washing, according to Leonard H. Calabrese, DO.

“Patients with rheumatic diseases have increased morbidity and mortality [from infection] and a lot of risk factors, including age, comorbidities, cytopenias, and extra-articular disease immunosuppression,” he said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Unfortunately, vaccination uptake remains “much lower than we would like in this country,” he said. Notably, influenza vaccination remains well below the World Health Organization target of 75%, he said.
 

Influenza vaccination

Flu vaccination will be even more important this year in the context of the COVID-19 pandemic, said Dr. Calabrese, professor of medicine and the RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic in Ohio. “For everyone who comes in with a respiratory illness, we will have to figure out whether it is flu or COVID,” he emphasized.

The Centers for Disease Control and Prevention recommendations include a detailed special considerations section for patients with immunocompromising conditions; “the notes have everything you need to know” about advising rheumatology patients, most of whom can safely receive a flu vaccine, he said.

One concern that always comes up is whether an antibody response will be suppressed based on therapy, Dr. Calabrese noted. Two major drugs with the greatest ability to reduce response are methotrexate and rituximab, he said. His tip: “Withhold methotrexate for two doses following seasonal flu vaccination.” This advice stems from a series of “practice-changing” studies by Park et al. published in 2017, 2018, and 2019 that showed benefit in withholding methotrexate for two doses following vaccination.

In the past, high-dose trivalent flu vaccines have been more expensive, and not necessarily practice changing, with studies showing varying clinical effectiveness and cost-effectiveness, Dr. Calabrese said. This year, a high-dose quadrivalent vaccine should be available that showed a 24% improvement in protection from all strains of influenza, compared with the standard vaccine in a head-to-head, randomized, controlled trial, he noted.

“All patients in rheumatology practices should get a flu vaccine,” with a 2-week hold on methotrexate following vaccination, he advised, and those aged 65 years and older should receive the high-dose quadrivalent. Younger patients on immunosuppressive therapy also might be considered for the high-dose vaccine, he said.

Pneumococcal vaccination

Dr. Calabrese also emphasized the value of pneumococcal vaccines for rheumatology patients. “The mortality for invasive disease ranges from 5% to 32%, but patients with immunocompromising conditions are at increased risk.”

Dr. Calabrese added a note on safety: Patients with cryopyrin-associated periodic syndrome (CAPS), a rare hereditary inflammatory disorder with cutaneous, neurologic, ophthalmologic, and rheumatologic manifestations, may have severe local and systemic reactions to the 23-valent polysaccharide vaccine (PPSV23), he said.

However, immunization against pneumococcal disease is safe and effective for most patients with autoimmune and inflammatory disorders regardless of their current therapy, he said. As with influenza, the CDC’s vaccination recommendations provide details for special situations, including immunocompromised individuals, he noted.

Dr. Calabrese recommended the 13-valent pneumococcal conjugate vaccine (PCV13) as soon as possible for rheumatology patients who have never been vaccinated, with follow-up doses of the 23-valent polysaccharide vaccine (PPSV23) at least 8 weeks later, and a PPSV23 booster 5 years after the first PPSV23 dose.
 

Protecting against shingles

When it comes to managing the varicella zoster virus (VZV) in immunocompromised patients, “prevention is preferable to treatment, as our patients are particularly vulnerable because of age and declining immunity,” Dr. Calabrese said.

Prevention is important because “once herpes zoster develops, the available treatments, including antiviral therapy, do not prevent postherpetic neuralgia in all patients,” he emphasized. “The treatments are complicated and not always effective,” he added.

The complications of zoster are well known, but recent data show an increased risk of cardiovascular disease as well, Dr. Calabrese said. “All the more reason to protect rheumatology patients from incident zoster,” he said.

Currently, the nonlive recombinant subunit zoster vaccine (Shingrix) is the preferred option for VZV vaccination according to the CDC’s Advisory Committee on Immunization Practices, Dr. Calabrese said. The CDC initially recommended its use to prevent herpes zoster and related complications in all immunocompetent adults aged 50 years and older; in an update, a C-level recommendation extends to “all patients aged 50 with or without immunosuppressive illnesses regardless of previous Zostavax exposure,” Dr. Calabrese said. “All patients on or starting [Janus] kinase inhibitors, regardless of age, should be considered” to receive the herpes zoster vaccine, he noted.

In general, promoting vaccination for rheumatology patients and for all patients is a multipronged effort that might include reminders, rewards, education, and standing orders, Dr. Calabrese said. Clinicians must continue to educate patients not only by strongly recommending the appropriate vaccines, but dispelling myths about vaccination, addressing fears, and providing current and accurate information, he said.

Dr. Calabrese disclosed relationships with AbbVie, Bristol-Myers Squibb, Crescendo, Genentech, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sanofi-Regeneron, and UCB.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

Systemic lupus erythematosus remains a treatment challenge, but a variety of drugs in the pipeline are set to target type I interferons, cytokines, and B cells, according to Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra University, Hempstead, N.Y.

Sara Freeman/MDedge News

In general, when treating patients with systemic lupus erythematosus (SLE), “we just don’t see satisfactory response rates,” Dr. Furie said in an online presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

“I think the greatest unmet need is in lupus nephritis,” he said. The data show that not even one-third of patients are adequately responding to standard of care treatment. “We need to do better in lupus nephritis but also for those patients with moderate-severe manifestations outside the kidney.”

Patients with SLE have elevated levels of interferon-alpha, Dr. Furie noted. Data from recent studies show that interferon inhibitors can reduce clinical activity in SLE patients, he said.

“About two-thirds to three-quarters of lupus patients have evidence of interferon pathway activation,” he said. There are three types of interferons, and five subtypes of type I interferon, and all five subtypes of type I interferon bind to the same receptor, which is an important strategy for drug development.

In particular, recent phase 2 and 3 trials have focused on targeting type I interferons with anifrolumab, which blocks all five subtypes.

Dr. Furie cited “very robust results” from a phase 2 study. Results of two phase 3 trials of anifrolumab led to a split decision, but the totality of the data collected across the phase 2 and 3 studies points to a drug that is effective for patients with SLE. The two phase 3 studies were published in Lancet Rheumatology and the New England Journal of Medicine.

Dr. Furie also identified recent studies of baricitinib (Olumiant), which has the ability to target several different cytokines. A phase 2 study in 2018 showed a significant difference in SLE Responder Index between lupus patients who received 4 mg of baricitinib or placebo, and a phase 3 study is underway, he said.

For lupus nephritis, Dr. Furie cited the BLISS-LN trial, a 104-week, randomized trial of patients with active lupus nephritis. The group of patients who received belimumab (Benlysta), a monoclonal antibody that targets B-cell activating factor, in addition to standard therapy had significant improvements in renal responses, compared with standard therapy alone (43.0% vs. 32.3%). The outcome measure was Primary Efficacy Renal Response, defined as urinary protein/creatinine ratio <0.7, eGFR ≥60 mL/min per 1.73 m², confirmation on consecutive visits, and required tapering of background glucocorticoids.

Although belimumab was approved for SLE in 2011, the BLISS-LN study focused on SLE patients with active kidney disease. “Neutralizing B-cell activating factor and down-regulating autoreactive B-cell function in kidneys represented a compelling therapeutic approach to lupus nephritis,” he explained.

Voclosporin, distinct from cyclosporine, has also been studied in lupus nephritis, Dr. Furie said. Voclosporin offers several benefits over cyclosporine, including greater potency and a lower drug and metabolite load, as well as a more consistent pharmacokinetic and pharmacodynamic relationship, he said. In the phase 3 AURORA study, presented at this year’s EULAR congress, 40% of patients with lupus nephritis met the primary endpoint of a renal response at 52 weeks, compared with 22.5% of placebo patients.

Looking ahead to the treatment of SLE in 2021, “I feel very strongly that voclosporin will be approved for lupus nephritis,” he said. He also predicted that the use of belimumab will be officially extended for lupus nephritis and that anifrolumab will receive an approval for SLE patients.

In addition, the future may witness the increased use of biomarkers and development of more individualized therapy. These breakthroughs will yield better outcomes for all lupus patients, he said.

Dr. Furie disclosed relationships with GlaxoSmithKline, Genentech/Roche, Aurinia Pharmaceuticals, AstraZeneca/MedImmune, and Eli Lilly. Global Academy for Medical Education and this news organization are owned by the same parent company.

Widespread treatment of hepatitis C virus significantly reduced the risk of hepatocellular carcinoma, based on 18 years of data from patients in Veterans Health Administration hospitals.

Although eradication of hepatitis C virus (HCV) infections has been shown to reduce the risk of hepatocellular carcinoma (HCC), effective direct-acting antiviral therapies available since 2013 appear underused in the United States, with a 14% cure rate for HCV patients as of 2016, wrote Lauren A. Beste, MD, of Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues.

However, “the Veterans Health Administration, the largest integrated health care system in the U.S., provides unrestricted access to HCV treatments and approximately 85% of its case load has achieved cure,” the researchers said.

In a letter published in JAMA, the researchers identified all patients in the VHA diagnosed with HCC based on electronic health records for each year between 2002 and 2018. HCV infection was based on any history of detectable viral load, and HCV cure was defined as a negative viral load at least 12 weeks following completion of antiviral treatment, the researchers said.

“We categorized patients into 3 groups as of the time of HCC diagnosis: HCC/HCV viremic (latest HCV RNA before HCC diagnosis was positive), HCC/HCV cured (HCV eradicated before HCC diagnosis), and HCC/non-HCV (no positive lifetime HCV RNA),” they explained.

The sum of HCC/HCV viremic plus HCC/HCV cured made up the HCC/HCV total. Overall, the incidence of HCC/HCV total increased from 2000 to 2015, peaked at 31.0 per 100,000 patients in 2015, and decreased to 21.8 per 100,000 in 2018 after the introduction of viral eradication efforts from 2014 to 2016.
 

HCV treatment shows value despite lack of causality

Although the study could not prove causality, “the timing of HCV eradication and declining HCC incidence, lack of decline in non–HCV-related HCC, and prior studies demonstrating that HCV eradication reduces HCC risk, provide indirect evidence that this decline may be related to widespread HCV treatment,” the researchers said.

The findings were limited by several factors including the observational study design, use of the International Classification of Diseases to define HCC, use of a VA population that might limit generalizability, and lack of data on the severity of disease prior to treatment, the researchers noted. However, “HCC incidence trends should continue to be monitored closely because patients cured of HCV may have yet to experience the full potential of risk reduction,” and the study results support large-scale campaigns to eliminate HCV as well as monitoring for HCC and HCV patients who achieve disease eradication, they concluded.

The study was supported in part by grants from the National Institutes of Health/National Cancer Institute and the Veterans Affairs Clinical Science Research and Development. The researchers had no financial conflicts to disclose.

SOURCE: Beste LA et al. JAMA. 2020 Sep 8;324(10):1003-5.

Widespread treatment of hepatitis C virus significantly reduced the risk of hepatocellular carcinoma, based on 18 years of data from patients in Veterans Health Administration hospitals.

Although eradication of hepatitis C virus (HCV) infections has been shown to reduce the risk of hepatocellular carcinoma (HCC), effective direct-acting antiviral therapies available since 2013 appear underused in the United States, with a 14% cure rate for HCV patients as of 2016, wrote Lauren A. Beste, MD, of Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues.

However, “the Veterans Health Administration, the largest integrated health care system in the U.S., provides unrestricted access to HCV treatments and approximately 85% of its case load has achieved cure,” the researchers said.

In a letter published in JAMA, the researchers identified all patients in the VHA diagnosed with HCC based on electronic health records for each year between 2002 and 2018. HCV infection was based on any history of detectable viral load, and HCV cure was defined as a negative viral load at least 12 weeks following completion of antiviral treatment, the researchers said.

“We categorized patients into 3 groups as of the time of HCC diagnosis: HCC/HCV viremic (latest HCV RNA before HCC diagnosis was positive), HCC/HCV cured (HCV eradicated before HCC diagnosis), and HCC/non-HCV (no positive lifetime HCV RNA),” they explained.

The sum of HCC/HCV viremic plus HCC/HCV cured made up the HCC/HCV total. Overall, the incidence of HCC/HCV total increased from 2000 to 2015, peaked at 31.0 per 100,000 patients in 2015, and decreased to 21.8 per 100,000 in 2018 after the introduction of viral eradication efforts from 2014 to 2016.
 

HCV treatment shows value despite lack of causality

Although the study could not prove causality, “the timing of HCV eradication and declining HCC incidence, lack of decline in non–HCV-related HCC, and prior studies demonstrating that HCV eradication reduces HCC risk, provide indirect evidence that this decline may be related to widespread HCV treatment,” the researchers said.

The findings were limited by several factors including the observational study design, use of the International Classification of Diseases to define HCC, use of a VA population that might limit generalizability, and lack of data on the severity of disease prior to treatment, the researchers noted. However, “HCC incidence trends should continue to be monitored closely because patients cured of HCV may have yet to experience the full potential of risk reduction,” and the study results support large-scale campaigns to eliminate HCV as well as monitoring for HCC and HCV patients who achieve disease eradication, they concluded.

The study was supported in part by grants from the National Institutes of Health/National Cancer Institute and the Veterans Affairs Clinical Science Research and Development. The researchers had no financial conflicts to disclose.

SOURCE: Beste LA et al. JAMA. 2020 Sep 8;324(10):1003-5.

Widespread treatment of hepatitis C virus significantly reduced the risk of hepatocellular carcinoma, based on 18 years of data from patients in Veterans Health Administration hospitals.

Although eradication of hepatitis C virus (HCV) infections has been shown to reduce the risk of hepatocellular carcinoma (HCC), effective direct-acting antiviral therapies available since 2013 appear underused in the United States, with a 14% cure rate for HCV patients as of 2016, wrote Lauren A. Beste, MD, of Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues.

However, “the Veterans Health Administration, the largest integrated health care system in the U.S., provides unrestricted access to HCV treatments and approximately 85% of its case load has achieved cure,” the researchers said.

In a letter published in JAMA, the researchers identified all patients in the VHA diagnosed with HCC based on electronic health records for each year between 2002 and 2018. HCV infection was based on any history of detectable viral load, and HCV cure was defined as a negative viral load at least 12 weeks following completion of antiviral treatment, the researchers said.

“We categorized patients into 3 groups as of the time of HCC diagnosis: HCC/HCV viremic (latest HCV RNA before HCC diagnosis was positive), HCC/HCV cured (HCV eradicated before HCC diagnosis), and HCC/non-HCV (no positive lifetime HCV RNA),” they explained.

The sum of HCC/HCV viremic plus HCC/HCV cured made up the HCC/HCV total. Overall, the incidence of HCC/HCV total increased from 2000 to 2015, peaked at 31.0 per 100,000 patients in 2015, and decreased to 21.8 per 100,000 in 2018 after the introduction of viral eradication efforts from 2014 to 2016.
 

HCV treatment shows value despite lack of causality

Although the study could not prove causality, “the timing of HCV eradication and declining HCC incidence, lack of decline in non–HCV-related HCC, and prior studies demonstrating that HCV eradication reduces HCC risk, provide indirect evidence that this decline may be related to widespread HCV treatment,” the researchers said.

The findings were limited by several factors including the observational study design, use of the International Classification of Diseases to define HCC, use of a VA population that might limit generalizability, and lack of data on the severity of disease prior to treatment, the researchers noted. However, “HCC incidence trends should continue to be monitored closely because patients cured of HCV may have yet to experience the full potential of risk reduction,” and the study results support large-scale campaigns to eliminate HCV as well as monitoring for HCC and HCV patients who achieve disease eradication, they concluded.

The study was supported in part by grants from the National Institutes of Health/National Cancer Institute and the Veterans Affairs Clinical Science Research and Development. The researchers had no financial conflicts to disclose.

SOURCE: Beste LA et al. JAMA. 2020 Sep 8;324(10):1003-5.

A history of liver transplant conveyed no increased risk of death from COVID-19 infections, according to data from a multicenter cohort study of 151 transplant recipients who became infected.

Although current data suggest a possible increased risk of adverse outcomes if liver transplant patients develop COVID-19 infections, the effects remain unclear, wrote Gwilym J. Webb, PhD, of the University of Oxford (England) and colleagues.

In a study published in the Lancet Gastroenterology & Hepatology, the researchers identified adults from 18 countries who had laboratory-confirmed COVID-19 infections between March 25, 2020, and June 26, 2020. The average age of the patients was 60 years, and 68% were men. A contemporaneous group of 627 consecutive adults with confirmed COVID-19 infections who had not undergone liver transplants served as controls.

Overall, 28 of the liver transplant patients and 167 of the controls died (19% vs. 27%; P = .046).

In addition, no differences appeared between infected transplant patients and infected controls in terms of hospitalization (82% vs. 76%) and the need for intensive care (31% vs. 30%), although the transplant patients were significantly more likely to require invasive ventilation (20% vs. 5%).

However, in a multivariate analysis, older age, serum creatinine concentration, and the presence of nonliver cancers were independently associated with increased risk of death in the liver transplant patients, with odds ratios of 1.06 for each year increase in age, 1.57 for each mg/dL increase in serum creatinine concentration, and 18.30 with the presence of a nonliver cancer.

The study findings were limited by several factors including the potential overreporting of severe COVID-19 cases because of reporting bias in the transplant registry, as well as the inability of the sample size to rule out mortality differences, the differences in comorbidities between the transplant patients and controls, and the impact of unmeasured confounding variables such as diet, physical activity, or fibrosis or cirrhosis in recipient grafts, the researchers noted. However, the results suggest that a history of liver transplantation does not increase the risk of death following COVID-19 infection, they wrote.

“Thus, traditional risk factors for adverse outcomes from COVID-19 should be preferentially considered when considering the risks and benefits of hospital attendance, immunosuppression, and social-distancing requirements for liver transplant recipients during the ongoing COVID-19 pandemic,” they concluded.

Focus on comorbidities and combined transplants

“Given that age and presence of comorbidities were significantly associated with risk of death in the cohorts of patients who had and had not undergone liver transplantation, greater emphasis should be placed on other coexisting comorbidities, rather than transplantation status per se, when risk-stratifying liver transplant recipients,” the researchers noted. “Indirectly, these findings suggest that liver transplantation, where indicated, should not be delayed during the COVID-19 pandemic, and that supportive care should not be limited for patients with existing liver transplants with COVID-19,” they suggested.

Given the high prevalence of COVID-19 in many countries, “it is inevitable that liver transplant patients will become infected,” said Wajahat Mehal, MD, of Yale University, New Haven, Conn., in an interview.

Going forward, “it is important to know the natural history of COVID in the immunocompromised population,” he emphasized.

One of the study limitations was the lack of data on how patients’ immunosuppression regimens were changed, if at all, while they were infected. “Since some other immunocompromised patients have had a higher rate of complications [in the wake of COVID-19 infections], I was pleasantly surprised that liver transplant recipients did so well,” Dr. Mehal said.

Dr. Mehal noted that additional research is needed to promote safety in patients with liver disease in the context of COVID-19. “It would be important to evaluate combined transplants, particularly combined liver/kidney transplants,” he said.

The study was supported by the European Association for the Study of the Liver, the National Institutes of Health, and the United Kingdom National Institute for Health Research. Lead author Dr. Webb had no financial conflicts to disclose. One coauthor disclosed unrelated fees from AbbVie and grants from the Fondation du Centre Hospitalier de l’Université de Montréal. Dr. Mehal had no financial conflicts to disclose.

SOURCE: Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Aug 28. doi: 10.1016/ S2468-1253(20)30271-5.

A history of liver transplant conveyed no increased risk of death from COVID-19 infections, according to data from a multicenter cohort study of 151 transplant recipients who became infected.

Although current data suggest a possible increased risk of adverse outcomes if liver transplant patients develop COVID-19 infections, the effects remain unclear, wrote Gwilym J. Webb, PhD, of the University of Oxford (England) and colleagues.

In a study published in the Lancet Gastroenterology & Hepatology, the researchers identified adults from 18 countries who had laboratory-confirmed COVID-19 infections between March 25, 2020, and June 26, 2020. The average age of the patients was 60 years, and 68% were men. A contemporaneous group of 627 consecutive adults with confirmed COVID-19 infections who had not undergone liver transplants served as controls.

Overall, 28 of the liver transplant patients and 167 of the controls died (19% vs. 27%; P = .046).

In addition, no differences appeared between infected transplant patients and infected controls in terms of hospitalization (82% vs. 76%) and the need for intensive care (31% vs. 30%), although the transplant patients were significantly more likely to require invasive ventilation (20% vs. 5%).

However, in a multivariate analysis, older age, serum creatinine concentration, and the presence of nonliver cancers were independently associated with increased risk of death in the liver transplant patients, with odds ratios of 1.06 for each year increase in age, 1.57 for each mg/dL increase in serum creatinine concentration, and 18.30 with the presence of a nonliver cancer.

The study findings were limited by several factors including the potential overreporting of severe COVID-19 cases because of reporting bias in the transplant registry, as well as the inability of the sample size to rule out mortality differences, the differences in comorbidities between the transplant patients and controls, and the impact of unmeasured confounding variables such as diet, physical activity, or fibrosis or cirrhosis in recipient grafts, the researchers noted. However, the results suggest that a history of liver transplantation does not increase the risk of death following COVID-19 infection, they wrote.

“Thus, traditional risk factors for adverse outcomes from COVID-19 should be preferentially considered when considering the risks and benefits of hospital attendance, immunosuppression, and social-distancing requirements for liver transplant recipients during the ongoing COVID-19 pandemic,” they concluded.

Focus on comorbidities and combined transplants

“Given that age and presence of comorbidities were significantly associated with risk of death in the cohorts of patients who had and had not undergone liver transplantation, greater emphasis should be placed on other coexisting comorbidities, rather than transplantation status per se, when risk-stratifying liver transplant recipients,” the researchers noted. “Indirectly, these findings suggest that liver transplantation, where indicated, should not be delayed during the COVID-19 pandemic, and that supportive care should not be limited for patients with existing liver transplants with COVID-19,” they suggested.

Given the high prevalence of COVID-19 in many countries, “it is inevitable that liver transplant patients will become infected,” said Wajahat Mehal, MD, of Yale University, New Haven, Conn., in an interview.

Going forward, “it is important to know the natural history of COVID in the immunocompromised population,” he emphasized.

One of the study limitations was the lack of data on how patients’ immunosuppression regimens were changed, if at all, while they were infected. “Since some other immunocompromised patients have had a higher rate of complications [in the wake of COVID-19 infections], I was pleasantly surprised that liver transplant recipients did so well,” Dr. Mehal said.

Dr. Mehal noted that additional research is needed to promote safety in patients with liver disease in the context of COVID-19. “It would be important to evaluate combined transplants, particularly combined liver/kidney transplants,” he said.

The study was supported by the European Association for the Study of the Liver, the National Institutes of Health, and the United Kingdom National Institute for Health Research. Lead author Dr. Webb had no financial conflicts to disclose. One coauthor disclosed unrelated fees from AbbVie and grants from the Fondation du Centre Hospitalier de l’Université de Montréal. Dr. Mehal had no financial conflicts to disclose.

SOURCE: Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Aug 28. doi: 10.1016/ S2468-1253(20)30271-5.

A history of liver transplant conveyed no increased risk of death from COVID-19 infections, according to data from a multicenter cohort study of 151 transplant recipients who became infected.

Although current data suggest a possible increased risk of adverse outcomes if liver transplant patients develop COVID-19 infections, the effects remain unclear, wrote Gwilym J. Webb, PhD, of the University of Oxford (England) and colleagues.

In a study published in the Lancet Gastroenterology & Hepatology, the researchers identified adults from 18 countries who had laboratory-confirmed COVID-19 infections between March 25, 2020, and June 26, 2020. The average age of the patients was 60 years, and 68% were men. A contemporaneous group of 627 consecutive adults with confirmed COVID-19 infections who had not undergone liver transplants served as controls.

Overall, 28 of the liver transplant patients and 167 of the controls died (19% vs. 27%; P = .046).

In addition, no differences appeared between infected transplant patients and infected controls in terms of hospitalization (82% vs. 76%) and the need for intensive care (31% vs. 30%), although the transplant patients were significantly more likely to require invasive ventilation (20% vs. 5%).

However, in a multivariate analysis, older age, serum creatinine concentration, and the presence of nonliver cancers were independently associated with increased risk of death in the liver transplant patients, with odds ratios of 1.06 for each year increase in age, 1.57 for each mg/dL increase in serum creatinine concentration, and 18.30 with the presence of a nonliver cancer.

The study findings were limited by several factors including the potential overreporting of severe COVID-19 cases because of reporting bias in the transplant registry, as well as the inability of the sample size to rule out mortality differences, the differences in comorbidities between the transplant patients and controls, and the impact of unmeasured confounding variables such as diet, physical activity, or fibrosis or cirrhosis in recipient grafts, the researchers noted. However, the results suggest that a history of liver transplantation does not increase the risk of death following COVID-19 infection, they wrote.

“Thus, traditional risk factors for adverse outcomes from COVID-19 should be preferentially considered when considering the risks and benefits of hospital attendance, immunosuppression, and social-distancing requirements for liver transplant recipients during the ongoing COVID-19 pandemic,” they concluded.

Focus on comorbidities and combined transplants

“Given that age and presence of comorbidities were significantly associated with risk of death in the cohorts of patients who had and had not undergone liver transplantation, greater emphasis should be placed on other coexisting comorbidities, rather than transplantation status per se, when risk-stratifying liver transplant recipients,” the researchers noted. “Indirectly, these findings suggest that liver transplantation, where indicated, should not be delayed during the COVID-19 pandemic, and that supportive care should not be limited for patients with existing liver transplants with COVID-19,” they suggested.

Given the high prevalence of COVID-19 in many countries, “it is inevitable that liver transplant patients will become infected,” said Wajahat Mehal, MD, of Yale University, New Haven, Conn., in an interview.

Going forward, “it is important to know the natural history of COVID in the immunocompromised population,” he emphasized.

One of the study limitations was the lack of data on how patients’ immunosuppression regimens were changed, if at all, while they were infected. “Since some other immunocompromised patients have had a higher rate of complications [in the wake of COVID-19 infections], I was pleasantly surprised that liver transplant recipients did so well,” Dr. Mehal said.

Dr. Mehal noted that additional research is needed to promote safety in patients with liver disease in the context of COVID-19. “It would be important to evaluate combined transplants, particularly combined liver/kidney transplants,” he said.

The study was supported by the European Association for the Study of the Liver, the National Institutes of Health, and the United Kingdom National Institute for Health Research. Lead author Dr. Webb had no financial conflicts to disclose. One coauthor disclosed unrelated fees from AbbVie and grants from the Fondation du Centre Hospitalier de l’Université de Montréal. Dr. Mehal had no financial conflicts to disclose.

SOURCE: Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Aug 28. doi: 10.1016/ S2468-1253(20)30271-5.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.

Early administration of evolocumab significantly reduced levels of LDL cholesterol in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention, according to data from an open-label randomized trial of 102 adults in Japan.

Data from previous studies have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce LDL cholesterol in acute coronary syndrome patients, wrote Tomoaki Okada, MD, of Kagawa (Japan) Prefectural Central Hospital and colleagues.

In particular, “The EVOPACS trial [J Am Coll Cardiol 2019; 74:2452-62] reported that evolocumab therapy initiated at an early phase of ACS showed [LDL cholesterol] level reduction by 4-8 weeks,” they said.

“However, the 4-week efficacy of PCSK9 inhibitor therapy combined with a statin remains unknown,” they said.

In a study presented at the virtual annual congress of the European Society of Cardiology and published simultaneously in JACC: Cardiovascular Interventions, the researchers randomized 52 patients to receive 140 mg of evolocumab subcutaneously within 24 hours of indexed percutaneous coronary intervention and again after 2 weeks. A group of 50 controls received evolocumab after PCI only, but no additional dose after 2 weeks.

The average age of the patients was 65 years, 88% were men, and 26% had a history of statin treatment.

A total of 49 patients in each group were included in the final analysis, with a primary outcome of change in LDL cholesterol levels from baseline to 4 weeks.

Baseline LCL cholesterol levels were 120.8 mg/dL and 124.7 mg/dL in the evolocumab and control groups, respectively. Changes from baseline were significantly greater in the evolocumab group, compared with controls, at –76% and –33%, respectively.

All patients in the evolocumab group and 27% of patients in the control groups achieved LDL cholesterol levels of less than 70 mg/dL at 4 weeks. In addition, 92% and 96% of evolocumab patients achieved LDL cholesterol levels less than 55 mg/dL at 2 weeks and 4 weeks, respectively.

Overall changes in non-HDL cholesterol, HDL cholesterol, and small dense LDL in the evolocumab and control groups were –66.2% and –26.0%; 2.8% and –0.7%; and –67% and –13.8%, respectively. Of these, changes in non-HDL cholesterol and small dense LDL were significantly different between the groups.

In addition, patients in the evolocumab group showed a 3% decrease in lipoprotein, compared with an 82% increase in the control group. This finding suggests the additional benefit of including evolocumab for managing residual risk in patients with high lipoprotein(a) levels” after acute MI, the researchers noted.

Adverse events and serious adverse events were similar between the groups.

‘Early and strong’ LDL cholesterol lowering best for preventing repeat events

“By using the PCSK9 inhibitors, we have the opportunity to lower LDL cholesterol [LDL-C]” both quickly and dramatically, said Heinz Drexel, MD, in an interview.

“This Japanese study shows that very low LDL-C levels can be obtained as fast as within 4 weeks,” he said. “This fits into the concept that risk for future infarctions and strokes is best reduced by early and strong LDL-C lowering,” he explained.

Dr. Drexel said that he was not surprised by the magnitude of the decrease in LDL cholesterol in study findings in light of the EVOPACS study and other research, as well as his own clinical experience.

“The primary message for doctors is that it is now possible to achieve these low levels of LDL-C in a short time,” he said.

“Additional research must prove that this low LDL-C translates to reduction of MIs and strokes, and there is increasing evidence that this will happen,” Dr. Drexel noted.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Drexel had no financial conflicts to disclose.

SOURCE: Okada T et al. ESC 2020. JACC Cardiovascular Interventions. 2020 Aug 28. doi: 10.1016/j.jcin.2020.08.026.

Early administration of evolocumab significantly reduced levels of LDL cholesterol in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention, according to data from an open-label randomized trial of 102 adults in Japan.

Data from previous studies have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce LDL cholesterol in acute coronary syndrome patients, wrote Tomoaki Okada, MD, of Kagawa (Japan) Prefectural Central Hospital and colleagues.

In particular, “The EVOPACS trial [J Am Coll Cardiol 2019; 74:2452-62] reported that evolocumab therapy initiated at an early phase of ACS showed [LDL cholesterol] level reduction by 4-8 weeks,” they said.

“However, the 4-week efficacy of PCSK9 inhibitor therapy combined with a statin remains unknown,” they said.

In a study presented at the virtual annual congress of the European Society of Cardiology and published simultaneously in JACC: Cardiovascular Interventions, the researchers randomized 52 patients to receive 140 mg of evolocumab subcutaneously within 24 hours of indexed percutaneous coronary intervention and again after 2 weeks. A group of 50 controls received evolocumab after PCI only, but no additional dose after 2 weeks.

The average age of the patients was 65 years, 88% were men, and 26% had a history of statin treatment.

A total of 49 patients in each group were included in the final analysis, with a primary outcome of change in LDL cholesterol levels from baseline to 4 weeks.

Baseline LCL cholesterol levels were 120.8 mg/dL and 124.7 mg/dL in the evolocumab and control groups, respectively. Changes from baseline were significantly greater in the evolocumab group, compared with controls, at –76% and –33%, respectively.

All patients in the evolocumab group and 27% of patients in the control groups achieved LDL cholesterol levels of less than 70 mg/dL at 4 weeks. In addition, 92% and 96% of evolocumab patients achieved LDL cholesterol levels less than 55 mg/dL at 2 weeks and 4 weeks, respectively.

Overall changes in non-HDL cholesterol, HDL cholesterol, and small dense LDL in the evolocumab and control groups were –66.2% and –26.0%; 2.8% and –0.7%; and –67% and –13.8%, respectively. Of these, changes in non-HDL cholesterol and small dense LDL were significantly different between the groups.

In addition, patients in the evolocumab group showed a 3% decrease in lipoprotein, compared with an 82% increase in the control group. This finding suggests the additional benefit of including evolocumab for managing residual risk in patients with high lipoprotein(a) levels” after acute MI, the researchers noted.

Adverse events and serious adverse events were similar between the groups.

‘Early and strong’ LDL cholesterol lowering best for preventing repeat events

“By using the PCSK9 inhibitors, we have the opportunity to lower LDL cholesterol [LDL-C]” both quickly and dramatically, said Heinz Drexel, MD, in an interview.

“This Japanese study shows that very low LDL-C levels can be obtained as fast as within 4 weeks,” he said. “This fits into the concept that risk for future infarctions and strokes is best reduced by early and strong LDL-C lowering,” he explained.

Dr. Drexel said that he was not surprised by the magnitude of the decrease in LDL cholesterol in study findings in light of the EVOPACS study and other research, as well as his own clinical experience.

“The primary message for doctors is that it is now possible to achieve these low levels of LDL-C in a short time,” he said.

“Additional research must prove that this low LDL-C translates to reduction of MIs and strokes, and there is increasing evidence that this will happen,” Dr. Drexel noted.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Drexel had no financial conflicts to disclose.

SOURCE: Okada T et al. ESC 2020. JACC Cardiovascular Interventions. 2020 Aug 28. doi: 10.1016/j.jcin.2020.08.026.

Early administration of evolocumab significantly reduced levels of LDL cholesterol in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention, according to data from an open-label randomized trial of 102 adults in Japan.

Data from previous studies have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can reduce LDL cholesterol in acute coronary syndrome patients, wrote Tomoaki Okada, MD, of Kagawa (Japan) Prefectural Central Hospital and colleagues.

In particular, “The EVOPACS trial [J Am Coll Cardiol 2019; 74:2452-62] reported that evolocumab therapy initiated at an early phase of ACS showed [LDL cholesterol] level reduction by 4-8 weeks,” they said.

“However, the 4-week efficacy of PCSK9 inhibitor therapy combined with a statin remains unknown,” they said.

In a study presented at the virtual annual congress of the European Society of Cardiology and published simultaneously in JACC: Cardiovascular Interventions, the researchers randomized 52 patients to receive 140 mg of evolocumab subcutaneously within 24 hours of indexed percutaneous coronary intervention and again after 2 weeks. A group of 50 controls received evolocumab after PCI only, but no additional dose after 2 weeks.

The average age of the patients was 65 years, 88% were men, and 26% had a history of statin treatment.

A total of 49 patients in each group were included in the final analysis, with a primary outcome of change in LDL cholesterol levels from baseline to 4 weeks.

Baseline LCL cholesterol levels were 120.8 mg/dL and 124.7 mg/dL in the evolocumab and control groups, respectively. Changes from baseline were significantly greater in the evolocumab group, compared with controls, at –76% and –33%, respectively.

All patients in the evolocumab group and 27% of patients in the control groups achieved LDL cholesterol levels of less than 70 mg/dL at 4 weeks. In addition, 92% and 96% of evolocumab patients achieved LDL cholesterol levels less than 55 mg/dL at 2 weeks and 4 weeks, respectively.

Overall changes in non-HDL cholesterol, HDL cholesterol, and small dense LDL in the evolocumab and control groups were –66.2% and –26.0%; 2.8% and –0.7%; and –67% and –13.8%, respectively. Of these, changes in non-HDL cholesterol and small dense LDL were significantly different between the groups.

In addition, patients in the evolocumab group showed a 3% decrease in lipoprotein, compared with an 82% increase in the control group. This finding suggests the additional benefit of including evolocumab for managing residual risk in patients with high lipoprotein(a) levels” after acute MI, the researchers noted.

Adverse events and serious adverse events were similar between the groups.

‘Early and strong’ LDL cholesterol lowering best for preventing repeat events

“By using the PCSK9 inhibitors, we have the opportunity to lower LDL cholesterol [LDL-C]” both quickly and dramatically, said Heinz Drexel, MD, in an interview.

“This Japanese study shows that very low LDL-C levels can be obtained as fast as within 4 weeks,” he said. “This fits into the concept that risk for future infarctions and strokes is best reduced by early and strong LDL-C lowering,” he explained.

Dr. Drexel said that he was not surprised by the magnitude of the decrease in LDL cholesterol in study findings in light of the EVOPACS study and other research, as well as his own clinical experience.

“The primary message for doctors is that it is now possible to achieve these low levels of LDL-C in a short time,” he said.

“Additional research must prove that this low LDL-C translates to reduction of MIs and strokes, and there is increasing evidence that this will happen,” Dr. Drexel noted.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Drexel had no financial conflicts to disclose.

SOURCE: Okada T et al. ESC 2020. JACC Cardiovascular Interventions. 2020 Aug 28. doi: 10.1016/j.jcin.2020.08.026.