Patients whose primary language is not English and who have a limited ability to read, speak, write, or understand English experience worse healthcare access than their English-speaking counterparts, highlighted by fewer healthcare visits and filled prescription medications.¹ These patients with limited English proficiency (LEP) face additional barriers to quality healthcare during the COVID-19 pandemic, including lower rates of telehealth use,² lower rates of COVID-19 testing,³ and challenges with implementing high-quality interpretation.⁴ As a result of such long-standing disparities, healthcare policy has focused on improving access to language-concordant care.

The Civil Rights Act of 1964 and Department of Health and Human Services (HHS) regulations require recipients of federal financial assistance to provide reasonable access to programs, services, and activities to persons with LEP. Section 1557 of the Affordable Care Act extends Title VI nondiscrimination standards to the entire healthcare system, including insurers and health plans. In 2016, the Obama administration implemented Section 1557 through regulations that clarified and expanded language accessibility standards, although several years later the Trump administration sought to weaken the rule’s protections.

Although the requirement to make healthcare accessible to patients with LEP is unequivocal, “reasonable access” provides clinicians who accept federal funds with flexibility in how they deliver language access services. Differing interpretations of what is considered “reasonable” drives variation in how and when medical facilities provide interpreter services. This results in inconsistency of services provided across care settings and decreased availability of language-concordant care. For example, less than one-third of outpatient providers regularly use qualified interpreters when seeing patients with LEP.⁵ Furthermore, only about 69% of hospitals offer language access services.⁶ Clinician underutilization of interpreters for patients with LEP results in poor patient satisfaction and worse health outcomes.⁷ In light of the Biden administration’s commitment to civil rights and healthcare access, we outline a roadmap of actions that this administration must take to ensure access to basic communication needs and improve health equity.

The Trump-era rules loosened the requirement that care providers notify patients with LEP of their rights to language services and provide instructions on how to access these services. These rules also allowed providers to replace video-based interpreter services with audio-based services, which disproportionately impacts patients in rural areas, who rely on high-quality video interpretation to facilitate telehealth visits, especially during the ongoing COVID-19 pandemic, which has increased patient reliance on telehealth infrastructure for primary healthcare access. The Trump administration weakened both the standards for ensuring adequate access to language assistance services and the compliance tests used to assess whether healthcare organizations have met those standards. The revised regulations deem certain healthcare services effectively exempt from interpreter standards if the projected number of encountered patients with LEP falls below preset minimums and a healthcare entity considers the cost of compliance onerous.⁸ The Trump administration justified these changes as a cost-savings matter, but the suboptimal care resulting from these changes will likely offset any savings.

To restore a strong commitment to language access, the HHS Office for Civil Rights, which the Biden administration has targeted for new investments in fiscal year 2022, should reestablish the HHS Language Access Steering Committee. This committee maintains criteria that guide covered health entities in developing language access compliance plans. Maintaining such plans should become a basic element of the revised Section 1557 compliance rules and should also become a core feature of the standards applicable to Joint Commission–accredited healthcare organizations. In addition, the Center for Medicare and Medicaid Innovation, whose mission is to identify, test, and implement major improvements in healthcare quality and efficiency, could undertake a special project to identify and incentivize adoption of the most effective language access innovations for incorporation into language access plans.

Section 1557, as well as federal standards governing the conditions of participation in federal healthcare programs, should ensure that covered entities report on interpreter use and associated patient health outcomes for patients with LEP. Overall compliance measurement and reporting in connection with language access is a matter of basic health equity. Currently, any individual who believes they have experienced discrimination based on language can report a potential violation for federal investigation. But an individual remedy is insufficient because it cannot ensure the types of systemic changes essential to overcome decades of structural exclusion and achieve broader health equity. Further, barriers from digital literacy gaps and fear of legal repercussions, such as deportation, hamper individual reporting efforts. Any policy focused on improving language access use should apply to all patients, regardless of immigration status.

Ultimately, there is little benefit to imposing standards without a concomitant assurance of the resources needed to achieve full adoption and ongoing compliance. For this reason, a commitment to language access must be accompanied by payment reforms that enable Medicare and Medicaid providers to embrace this vital feature of accessible healthcare by recognizing interpreter costs as part of the clinical encounter and care management. Covered entities could use these resources either to strengthen their own staffing or contract with third-party interpreter services organizations. Currently, the Centers for Medicare & Medicaid Services (CMS) allow states to claim federal matching funds for language assistance services provided to Medicaid enrollees, though rates are dependent on how service claims are categorized. State Medicaid programs can facilitate the provision of such services by optimizing reimbursements for provider organizations under CMS policy.

The Merit-based Incentive Payment System (MIPS) provides an opportunity to incorporate the provision of interpreter services into quality measure reporting. Such efforts could improve health equity and address long-standing needs for research into how language barriers affect healthcare outcomes. Given that analyses of inaugural MIPS data revealed that safety-net practices were more likely to receive lower composite scores, additional scoring flexibility under pay-for-performance schemes (rather than strict penalties) may be necessary to ensure the solvency of safety net practices that disproportionately care for patients with LEP.⁹ Here, CMMI can play a critical role in expanding the use of patient-facing resources by designing new alternative payment models that reward participants for providing high-quality language concordant care.

The COVID-19 pandemic has exacerbated disparities in care for patients with LEP and even starker disparities among immigrant communities and patients of color. These disparities will only worsen if regulations aimed at improving access to language access services are not reinstated and improved. Failing to focus on healthcare access for patients with LEP hurts individual patient health and public health, as we have seen through lower rates of testing and vaccination in communities of color during this pandemic. The Biden administration can put healthcare on a more equitable pathway by expanding and strengthening language access as a core feature of healthcare, as a matter of both civil rights and health care quality.

The authors thank Jocelyn Samuels, JD, and Sara Rosenbaum, JD, for comments and guidance on an earlier draft of this article.

Patients whose primary language is not English and who have a limited ability to read, speak, write, or understand English experience worse healthcare access than their English-speaking counterparts, highlighted by fewer healthcare visits and filled prescription medications.¹ These patients with limited English proficiency (LEP) face additional barriers to quality healthcare during the COVID-19 pandemic, including lower rates of telehealth use,² lower rates of COVID-19 testing,³ and challenges with implementing high-quality interpretation.⁴ As a result of such long-standing disparities, healthcare policy has focused on improving access to language-concordant care.

The Civil Rights Act of 1964 and Department of Health and Human Services (HHS) regulations require recipients of federal financial assistance to provide reasonable access to programs, services, and activities to persons with LEP. Section 1557 of the Affordable Care Act extends Title VI nondiscrimination standards to the entire healthcare system, including insurers and health plans. In 2016, the Obama administration implemented Section 1557 through regulations that clarified and expanded language accessibility standards, although several years later the Trump administration sought to weaken the rule’s protections.

Although the requirement to make healthcare accessible to patients with LEP is unequivocal, “reasonable access” provides clinicians who accept federal funds with flexibility in how they deliver language access services. Differing interpretations of what is considered “reasonable” drives variation in how and when medical facilities provide interpreter services. This results in inconsistency of services provided across care settings and decreased availability of language-concordant care. For example, less than one-third of outpatient providers regularly use qualified interpreters when seeing patients with LEP.⁵ Furthermore, only about 69% of hospitals offer language access services.⁶ Clinician underutilization of interpreters for patients with LEP results in poor patient satisfaction and worse health outcomes.⁷ In light of the Biden administration’s commitment to civil rights and healthcare access, we outline a roadmap of actions that this administration must take to ensure access to basic communication needs and improve health equity.

The Trump-era rules loosened the requirement that care providers notify patients with LEP of their rights to language services and provide instructions on how to access these services. These rules also allowed providers to replace video-based interpreter services with audio-based services, which disproportionately impacts patients in rural areas, who rely on high-quality video interpretation to facilitate telehealth visits, especially during the ongoing COVID-19 pandemic, which has increased patient reliance on telehealth infrastructure for primary healthcare access. The Trump administration weakened both the standards for ensuring adequate access to language assistance services and the compliance tests used to assess whether healthcare organizations have met those standards. The revised regulations deem certain healthcare services effectively exempt from interpreter standards if the projected number of encountered patients with LEP falls below preset minimums and a healthcare entity considers the cost of compliance onerous.⁸ The Trump administration justified these changes as a cost-savings matter, but the suboptimal care resulting from these changes will likely offset any savings.

To restore a strong commitment to language access, the HHS Office for Civil Rights, which the Biden administration has targeted for new investments in fiscal year 2022, should reestablish the HHS Language Access Steering Committee. This committee maintains criteria that guide covered health entities in developing language access compliance plans. Maintaining such plans should become a basic element of the revised Section 1557 compliance rules and should also become a core feature of the standards applicable to Joint Commission–accredited healthcare organizations. In addition, the Center for Medicare and Medicaid Innovation, whose mission is to identify, test, and implement major improvements in healthcare quality and efficiency, could undertake a special project to identify and incentivize adoption of the most effective language access innovations for incorporation into language access plans.

Section 1557, as well as federal standards governing the conditions of participation in federal healthcare programs, should ensure that covered entities report on interpreter use and associated patient health outcomes for patients with LEP. Overall compliance measurement and reporting in connection with language access is a matter of basic health equity. Currently, any individual who believes they have experienced discrimination based on language can report a potential violation for federal investigation. But an individual remedy is insufficient because it cannot ensure the types of systemic changes essential to overcome decades of structural exclusion and achieve broader health equity. Further, barriers from digital literacy gaps and fear of legal repercussions, such as deportation, hamper individual reporting efforts. Any policy focused on improving language access use should apply to all patients, regardless of immigration status.

Ultimately, there is little benefit to imposing standards without a concomitant assurance of the resources needed to achieve full adoption and ongoing compliance. For this reason, a commitment to language access must be accompanied by payment reforms that enable Medicare and Medicaid providers to embrace this vital feature of accessible healthcare by recognizing interpreter costs as part of the clinical encounter and care management. Covered entities could use these resources either to strengthen their own staffing or contract with third-party interpreter services organizations. Currently, the Centers for Medicare & Medicaid Services (CMS) allow states to claim federal matching funds for language assistance services provided to Medicaid enrollees, though rates are dependent on how service claims are categorized. State Medicaid programs can facilitate the provision of such services by optimizing reimbursements for provider organizations under CMS policy.

The Merit-based Incentive Payment System (MIPS) provides an opportunity to incorporate the provision of interpreter services into quality measure reporting. Such efforts could improve health equity and address long-standing needs for research into how language barriers affect healthcare outcomes. Given that analyses of inaugural MIPS data revealed that safety-net practices were more likely to receive lower composite scores, additional scoring flexibility under pay-for-performance schemes (rather than strict penalties) may be necessary to ensure the solvency of safety net practices that disproportionately care for patients with LEP.⁹ Here, CMMI can play a critical role in expanding the use of patient-facing resources by designing new alternative payment models that reward participants for providing high-quality language concordant care.

The COVID-19 pandemic has exacerbated disparities in care for patients with LEP and even starker disparities among immigrant communities and patients of color. These disparities will only worsen if regulations aimed at improving access to language access services are not reinstated and improved. Failing to focus on healthcare access for patients with LEP hurts individual patient health and public health, as we have seen through lower rates of testing and vaccination in communities of color during this pandemic. The Biden administration can put healthcare on a more equitable pathway by expanding and strengthening language access as a core feature of healthcare, as a matter of both civil rights and health care quality.

The authors thank Jocelyn Samuels, JD, and Sara Rosenbaum, JD, for comments and guidance on an earlier draft of this article.

Patients whose primary language is not English and who have a limited ability to read, speak, write, or understand English experience worse healthcare access than their English-speaking counterparts, highlighted by fewer healthcare visits and filled prescription medications.¹ These patients with limited English proficiency (LEP) face additional barriers to quality healthcare during the COVID-19 pandemic, including lower rates of telehealth use,² lower rates of COVID-19 testing,³ and challenges with implementing high-quality interpretation.⁴ As a result of such long-standing disparities, healthcare policy has focused on improving access to language-concordant care.

The Civil Rights Act of 1964 and Department of Health and Human Services (HHS) regulations require recipients of federal financial assistance to provide reasonable access to programs, services, and activities to persons with LEP. Section 1557 of the Affordable Care Act extends Title VI nondiscrimination standards to the entire healthcare system, including insurers and health plans. In 2016, the Obama administration implemented Section 1557 through regulations that clarified and expanded language accessibility standards, although several years later the Trump administration sought to weaken the rule’s protections.

Although the requirement to make healthcare accessible to patients with LEP is unequivocal, “reasonable access” provides clinicians who accept federal funds with flexibility in how they deliver language access services. Differing interpretations of what is considered “reasonable” drives variation in how and when medical facilities provide interpreter services. This results in inconsistency of services provided across care settings and decreased availability of language-concordant care. For example, less than one-third of outpatient providers regularly use qualified interpreters when seeing patients with LEP.⁵ Furthermore, only about 69% of hospitals offer language access services.⁶ Clinician underutilization of interpreters for patients with LEP results in poor patient satisfaction and worse health outcomes.⁷ In light of the Biden administration’s commitment to civil rights and healthcare access, we outline a roadmap of actions that this administration must take to ensure access to basic communication needs and improve health equity.

The Trump-era rules loosened the requirement that care providers notify patients with LEP of their rights to language services and provide instructions on how to access these services. These rules also allowed providers to replace video-based interpreter services with audio-based services, which disproportionately impacts patients in rural areas, who rely on high-quality video interpretation to facilitate telehealth visits, especially during the ongoing COVID-19 pandemic, which has increased patient reliance on telehealth infrastructure for primary healthcare access. The Trump administration weakened both the standards for ensuring adequate access to language assistance services and the compliance tests used to assess whether healthcare organizations have met those standards. The revised regulations deem certain healthcare services effectively exempt from interpreter standards if the projected number of encountered patients with LEP falls below preset minimums and a healthcare entity considers the cost of compliance onerous.⁸ The Trump administration justified these changes as a cost-savings matter, but the suboptimal care resulting from these changes will likely offset any savings.

To restore a strong commitment to language access, the HHS Office for Civil Rights, which the Biden administration has targeted for new investments in fiscal year 2022, should reestablish the HHS Language Access Steering Committee. This committee maintains criteria that guide covered health entities in developing language access compliance plans. Maintaining such plans should become a basic element of the revised Section 1557 compliance rules and should also become a core feature of the standards applicable to Joint Commission–accredited healthcare organizations. In addition, the Center for Medicare and Medicaid Innovation, whose mission is to identify, test, and implement major improvements in healthcare quality and efficiency, could undertake a special project to identify and incentivize adoption of the most effective language access innovations for incorporation into language access plans.

Section 1557, as well as federal standards governing the conditions of participation in federal healthcare programs, should ensure that covered entities report on interpreter use and associated patient health outcomes for patients with LEP. Overall compliance measurement and reporting in connection with language access is a matter of basic health equity. Currently, any individual who believes they have experienced discrimination based on language can report a potential violation for federal investigation. But an individual remedy is insufficient because it cannot ensure the types of systemic changes essential to overcome decades of structural exclusion and achieve broader health equity. Further, barriers from digital literacy gaps and fear of legal repercussions, such as deportation, hamper individual reporting efforts. Any policy focused on improving language access use should apply to all patients, regardless of immigration status.

Ultimately, there is little benefit to imposing standards without a concomitant assurance of the resources needed to achieve full adoption and ongoing compliance. For this reason, a commitment to language access must be accompanied by payment reforms that enable Medicare and Medicaid providers to embrace this vital feature of accessible healthcare by recognizing interpreter costs as part of the clinical encounter and care management. Covered entities could use these resources either to strengthen their own staffing or contract with third-party interpreter services organizations. Currently, the Centers for Medicare & Medicaid Services (CMS) allow states to claim federal matching funds for language assistance services provided to Medicaid enrollees, though rates are dependent on how service claims are categorized. State Medicaid programs can facilitate the provision of such services by optimizing reimbursements for provider organizations under CMS policy.

The Merit-based Incentive Payment System (MIPS) provides an opportunity to incorporate the provision of interpreter services into quality measure reporting. Such efforts could improve health equity and address long-standing needs for research into how language barriers affect healthcare outcomes. Given that analyses of inaugural MIPS data revealed that safety-net practices were more likely to receive lower composite scores, additional scoring flexibility under pay-for-performance schemes (rather than strict penalties) may be necessary to ensure the solvency of safety net practices that disproportionately care for patients with LEP.⁹ Here, CMMI can play a critical role in expanding the use of patient-facing resources by designing new alternative payment models that reward participants for providing high-quality language concordant care.

The COVID-19 pandemic has exacerbated disparities in care for patients with LEP and even starker disparities among immigrant communities and patients of color. These disparities will only worsen if regulations aimed at improving access to language access services are not reinstated and improved. Failing to focus on healthcare access for patients with LEP hurts individual patient health and public health, as we have seen through lower rates of testing and vaccination in communities of color during this pandemic. The Biden administration can put healthcare on a more equitable pathway by expanding and strengthening language access as a core feature of healthcare, as a matter of both civil rights and health care quality.

The authors thank Jocelyn Samuels, JD, and Sara Rosenbaum, JD, for comments and guidance on an earlier draft of this article.

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

A version of this article first appeared on Medscape.com.

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

A version of this article first appeared on Medscape.com.

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

A version of this article first appeared on Medscape.com.

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

A version of this article first appeared on Medscape.com.

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

A version of this article first appeared on Medscape.com.

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

A version of this article first appeared on Medscape.com.

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

rfranki@mdedge.com

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

rfranki@mdedge.com

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

rfranki@mdedge.com

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

A version of this article first appeared on WebMD.com.

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

A version of this article first appeared on WebMD.com.

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

A version of this article first appeared on WebMD.com.

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.