The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

Women who take a wide variety of disease-modifying therapies (DMTs) for multiple sclerosis (MS) – not just those on a few types – may be especially susceptible to hair loss via alopecia, a new study finds.

From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.

“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”

According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”

Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).

The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.

Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.

Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”

The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”

Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.

Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”

No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.

Women who take a wide variety of disease-modifying therapies (DMTs) for multiple sclerosis (MS) – not just those on a few types – may be especially susceptible to hair loss via alopecia, a new study finds.

From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.

“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”

According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”

Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).

The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.

Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.

Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”

The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”

Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.

Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”

No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.

Women who take a wide variety of disease-modifying therapies (DMTs) for multiple sclerosis (MS) – not just those on a few types – may be especially susceptible to hair loss via alopecia, a new study finds.

From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.

“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”

According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”

Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).

The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.

Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.

Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”

The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”

Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.

Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”

No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.

It’s undeniable that great strides have been made in advancing the science of multiple sclerosis (MS) over the past 20 years. Continued pursuit of research and discovery has revolutionized the understanding, diagnosis, and treatment of this debilitating condition that causes symptoms that may impact nearly every part of the body and mind. Despite these advancements, there is still more work to be done.

As the search for a cure continues, it’s imperative to ask the big questions: How does MS develop and progress? How can we reduce health disparities in care and treatment? How can we improve existing treatments and expedite the discovery of new ones? To continue making progress, we must stretch the boundaries of scientific understanding until we have answers and solutions to these and other important questions.

We know that MS is a leading cause of non-traumatic disability for young people.^1,2 Yet, one of the biggest challenges for neurologists is that every person’s experience with MS is unique, making it difficult to predict what symptoms will manifest, how disruptive the symptoms and relapses will be and how a person will respond to treatment.

Twenty years ago, it was widely thought that MS was mainly driven by T cells, but in the late 1990’s, a team of researchers made a groundbreaking discovery: B cells also played a key role in MS. This discovery redefined how the scientific community thought about the underlying biology of MS and the central role B cells can play. 

It was this bold thinking that led researchers at the University of California, San Francisco (UCSF) and scientists at Genentech, a member of the Roche Group, to explore whether a medication that depleted B cells would have an impact on MS. This collaboration, in turn, inspired the clinical research behind Ocrevus^® (ocrelizumab), the first and only treatment approved by the FDA for both relapsing MS (RMS) and primary progressive MS (PPMS). MS is a progressive disease from the start. An important goal of treating MS is to reduce disease progression as soon as possible to slow how quickly a person’s disability changes and prevent the long-term consequences of disease progression.³ Ocrevus is administered via infusion twice yearly, with the initial dose split into two separate infusions and given two weeks apart. As with any therapy, this treatment has side effects, which can be found in the full Prescribing Information and Medication Guide. Ocrevus is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reactions to Ocrevus. The warnings and precautions for Ocrevus are infusion reactions, and infections, which include respiratory tract infections, herpes, progressive multifocal leukoencephalopathy (PML), and hepatitis B virus (HBV) reactivation. Additional warnings are possible increased risk of immunosuppressant effects with other immunosuppressants, reduction in immunoglobulins, and malignancies.

Ensuring a Continuum of Care 
Another significant challenge facing the MS community is ensuring ongoing support and care for people living with the condition, especially throughout the COVID-19 pandemic. “We know that seeking early and appropriate care for MS is critical to slowing disability progression and achieving successful patient outcomes,” said Dr. Ashish Pradhan, Executive Director of Neuroimmunology at Genentech. “The pandemic has created additional barriers to early diagnosis and treatment, but we are committed to continuing to do everything we can to support patients and physicians at this stressful time.” Dr. Pradhan also observed that FDA's approval of a shorter infusion time for Ocrevus in December 2020 could potentially contribute to reducing some of the burden on the healthcare system in the long-term.

Being able to connect with others in the MS community is a vital part of navigating the uncertainties of living with the condition. This past April, to shine a light on the diverse MS community, Genentech hosted an #MSVisibility Virtual Concert that gathered people from across the world with different backgrounds and MS experiences and encouraged people living with MS to continue seeking appropriate support and care during the pandemic.

Continued support of the MS community through advocacy partnerships and grants over the years has played a sustained role in Genentech’s efforts to ensure people with MS receive necessary medical care and treatment. For example, Genentech partnered with an MS advocacy organization to fund a program that helps people get to and from their medical appointments. In addition, for more than 30 years, Genentech has helped more than two million people get the medicine they need through patient assistance programs like Genentech Access Solutions and the Genentech Patient Foundation.

Advancing Inclusive Research in MS 
MS has been shown to impact individuals and specific populations in markedly different ways. Those who identify as Black or of African descent and Hispanic/Latinos for example can experience more severe symptoms and faster disease progression than their Caucasian counterparts.^4,5 Unfortunately, it’s not clear exactly why, largely because of their vast underrepresentation in clinical trials (less than 5% and 1%, respectively).⁶ While there are multiple explanations for these disparities, around one-in-three minority patients don’t participate in clinical trials due to lack of trust and 52% feel that the healthcare system is not only flawed, but is actually working against them.⁷

“Increased diversity in research is paramount to ensuring that the healthcare system is serving every person living with MS and ultimately reducing health inequities while providing more tailored treatment options,” commented Dr. Pradhan. “To advance the care of undertreated and underserved people with MS, we are creating and supporting programs, grants and other initiatives focused on people of color and inclusive and minority research to better understand how MS presents itself and develops in different patient populations. We want to make sure that all generations of people living with MS are equally represented in clinical research and have access to the treatments that will work best for them.”

Refining Existing Approaches and Leading Treatment Innovation
For decades, Genentech and Roche have been conducting neuroscience research and clinical trials to make forward progress in understanding and treating a variety of neurological conditions, including MS. While the treatment landscape for MS has evolved significantly over the past two decades, continued investment in research and development is critical. Continuing to review and refine existing treatment approaches may improve patient outcomes and discovering new treatment approaches may play an important role in advancing the treatment paradigm.

Dr. Pradhan added, “as the scientific community continues to think boldly, and re-imagine treatment and care for MS, we hope to continue to improve our understanding of the condition for all people with the disease, and advance treatment options. Pushing boundaries means refusing to stop until everyone living with MS can be treated effectively and a cure is found. This sentiment reminds me of a Ralph Waldo Emerson quote, ‘Don’t follow where the path may lead. Go instead where there is no path and leave a trail.’ That’s what we are trying to do at Genentech.”

To learn more, please visit Ocrevus.com.

Indications and Important Safety Information
OCREVUS is indicated for the treatment of:

• Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
• Primary progressive MS, in adults. 

Contraindications
OCREVUS is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reaction to OCREVUS.

Warnings and Precautions

Infusion Reactions  

OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34-40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.  

Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections

A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. OCREVUS was not associated with an increased risk of serious infections in MS patients. Delay OCREVUS administration in patients with an active infection until the infection is resolved.

Respiratory Tract Infections

A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-treated patients than in the patients on placebo (2.7% vs 0.8%).

Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving OCREVUS. Serious herpes virus infections may occur at any time during treatment with OCREVUS. Some cases were life-threatening. 

If serious herpes infections occur, OCREVUS should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered.

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes (per USPI).

Hepatitis B Virus (HBV) Reactivation

Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effect. OCREVUS has not been studied in combination with other MS therapies.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy

In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Malignancies  

An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.

Use in Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to OCREVUS during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.

There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to OCREVUS. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. 

Lactation 

There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition.

Females and Males of Reproductive Potential

Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS.

Most Common Adverse Reactions

RMS: The most common adverse reactions in RMS trials (incidence ≥10% and >REBIF) were upper respiratory tract infections (40%) and infusion reactions (34%).
 

PPMS: The most common adverse reactions in PPMS trials (incidence ≥10% and >placebo) were upper respiratory tract infections (49%), infusion reactions (40%), skin infections (14%), and lower respiratory tract infections (10%).

For additional safety information, please see the full Prescribing Information and Medication Guide.

¹ Murray TJ. (2006). Diagnosis and Treatment of Multiple Sclerosis. BMJ, 322 (7540):525-527.
² Tullman M. (2013). Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis. The American Journal of Managed Care. 19 (2): S15-S20.
³ National Institutes of Health-National Institute of Neurological Disorders and Stroke. (2015). Multiple Sclerosis: Hope Through Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research.
⁴ National MS Society. "Who Gets MS? - African Americans." Retrieved November 2020. nationalmssociety.org/What-is-MS/Who-Gets-MS/African-American-Resources.
⁵ Langer-Gould A, et al. Neurology. 2013;80:1734-1739; 2. Wallin MT, et al. Brain. 2012;135:1778-1785.
⁶ U.S. Food and Drug Administration. “Clinical Trials Shed Light on Minority Health.” U.S. Food and Drug Administration Website. https://wayback.archive-it.org/7993/20180908114418/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm349063.htm. Published 2018.
⁷ Genentech. “A New Perspective on Health Inequity.” https://www.gene.com/stories/a-new-perspective-on-health-inequity.

It’s undeniable that great strides have been made in advancing the science of multiple sclerosis (MS) over the past 20 years. Continued pursuit of research and discovery has revolutionized the understanding, diagnosis, and treatment of this debilitating condition that causes symptoms that may impact nearly every part of the body and mind. Despite these advancements, there is still more work to be done.

As the search for a cure continues, it’s imperative to ask the big questions: How does MS develop and progress? How can we reduce health disparities in care and treatment? How can we improve existing treatments and expedite the discovery of new ones? To continue making progress, we must stretch the boundaries of scientific understanding until we have answers and solutions to these and other important questions.

We know that MS is a leading cause of non-traumatic disability for young people.^1,2 Yet, one of the biggest challenges for neurologists is that every person’s experience with MS is unique, making it difficult to predict what symptoms will manifest, how disruptive the symptoms and relapses will be and how a person will respond to treatment.

Twenty years ago, it was widely thought that MS was mainly driven by T cells, but in the late 1990’s, a team of researchers made a groundbreaking discovery: B cells also played a key role in MS. This discovery redefined how the scientific community thought about the underlying biology of MS and the central role B cells can play. 

It was this bold thinking that led researchers at the University of California, San Francisco (UCSF) and scientists at Genentech, a member of the Roche Group, to explore whether a medication that depleted B cells would have an impact on MS. This collaboration, in turn, inspired the clinical research behind Ocrevus^® (ocrelizumab), the first and only treatment approved by the FDA for both relapsing MS (RMS) and primary progressive MS (PPMS). MS is a progressive disease from the start. An important goal of treating MS is to reduce disease progression as soon as possible to slow how quickly a person’s disability changes and prevent the long-term consequences of disease progression.³ Ocrevus is administered via infusion twice yearly, with the initial dose split into two separate infusions and given two weeks apart. As with any therapy, this treatment has side effects, which can be found in the full Prescribing Information and Medication Guide. Ocrevus is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reactions to Ocrevus. The warnings and precautions for Ocrevus are infusion reactions, and infections, which include respiratory tract infections, herpes, progressive multifocal leukoencephalopathy (PML), and hepatitis B virus (HBV) reactivation. Additional warnings are possible increased risk of immunosuppressant effects with other immunosuppressants, reduction in immunoglobulins, and malignancies.

Ensuring a Continuum of Care 
Another significant challenge facing the MS community is ensuring ongoing support and care for people living with the condition, especially throughout the COVID-19 pandemic. “We know that seeking early and appropriate care for MS is critical to slowing disability progression and achieving successful patient outcomes,” said Dr. Ashish Pradhan, Executive Director of Neuroimmunology at Genentech. “The pandemic has created additional barriers to early diagnosis and treatment, but we are committed to continuing to do everything we can to support patients and physicians at this stressful time.” Dr. Pradhan also observed that FDA's approval of a shorter infusion time for Ocrevus in December 2020 could potentially contribute to reducing some of the burden on the healthcare system in the long-term.

Being able to connect with others in the MS community is a vital part of navigating the uncertainties of living with the condition. This past April, to shine a light on the diverse MS community, Genentech hosted an #MSVisibility Virtual Concert that gathered people from across the world with different backgrounds and MS experiences and encouraged people living with MS to continue seeking appropriate support and care during the pandemic.

Continued support of the MS community through advocacy partnerships and grants over the years has played a sustained role in Genentech’s efforts to ensure people with MS receive necessary medical care and treatment. For example, Genentech partnered with an MS advocacy organization to fund a program that helps people get to and from their medical appointments. In addition, for more than 30 years, Genentech has helped more than two million people get the medicine they need through patient assistance programs like Genentech Access Solutions and the Genentech Patient Foundation.

Advancing Inclusive Research in MS 
MS has been shown to impact individuals and specific populations in markedly different ways. Those who identify as Black or of African descent and Hispanic/Latinos for example can experience more severe symptoms and faster disease progression than their Caucasian counterparts.^4,5 Unfortunately, it’s not clear exactly why, largely because of their vast underrepresentation in clinical trials (less than 5% and 1%, respectively).⁶ While there are multiple explanations for these disparities, around one-in-three minority patients don’t participate in clinical trials due to lack of trust and 52% feel that the healthcare system is not only flawed, but is actually working against them.⁷

“Increased diversity in research is paramount to ensuring that the healthcare system is serving every person living with MS and ultimately reducing health inequities while providing more tailored treatment options,” commented Dr. Pradhan. “To advance the care of undertreated and underserved people with MS, we are creating and supporting programs, grants and other initiatives focused on people of color and inclusive and minority research to better understand how MS presents itself and develops in different patient populations. We want to make sure that all generations of people living with MS are equally represented in clinical research and have access to the treatments that will work best for them.”

Refining Existing Approaches and Leading Treatment Innovation
For decades, Genentech and Roche have been conducting neuroscience research and clinical trials to make forward progress in understanding and treating a variety of neurological conditions, including MS. While the treatment landscape for MS has evolved significantly over the past two decades, continued investment in research and development is critical. Continuing to review and refine existing treatment approaches may improve patient outcomes and discovering new treatment approaches may play an important role in advancing the treatment paradigm.

Dr. Pradhan added, “as the scientific community continues to think boldly, and re-imagine treatment and care for MS, we hope to continue to improve our understanding of the condition for all people with the disease, and advance treatment options. Pushing boundaries means refusing to stop until everyone living with MS can be treated effectively and a cure is found. This sentiment reminds me of a Ralph Waldo Emerson quote, ‘Don’t follow where the path may lead. Go instead where there is no path and leave a trail.’ That’s what we are trying to do at Genentech.”

To learn more, please visit Ocrevus.com.

Indications and Important Safety Information
OCREVUS is indicated for the treatment of:

• Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
• Primary progressive MS, in adults. 

Contraindications
OCREVUS is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reaction to OCREVUS.

Warnings and Precautions

Infusion Reactions  

OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34-40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.  

Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections

A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. OCREVUS was not associated with an increased risk of serious infections in MS patients. Delay OCREVUS administration in patients with an active infection until the infection is resolved.

Respiratory Tract Infections

A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-treated patients than in the patients on placebo (2.7% vs 0.8%).

Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving OCREVUS. Serious herpes virus infections may occur at any time during treatment with OCREVUS. Some cases were life-threatening. 

If serious herpes infections occur, OCREVUS should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered.

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes (per USPI).

Hepatitis B Virus (HBV) Reactivation

Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effect. OCREVUS has not been studied in combination with other MS therapies.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy

In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Malignancies  

An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.

Use in Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to OCREVUS during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.

There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to OCREVUS. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. 

Lactation 

There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition.

Females and Males of Reproductive Potential

Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS.

Most Common Adverse Reactions

RMS: The most common adverse reactions in RMS trials (incidence ≥10% and >REBIF) were upper respiratory tract infections (40%) and infusion reactions (34%).
 

PPMS: The most common adverse reactions in PPMS trials (incidence ≥10% and >placebo) were upper respiratory tract infections (49%), infusion reactions (40%), skin infections (14%), and lower respiratory tract infections (10%).

For additional safety information, please see the full Prescribing Information and Medication Guide.

¹ Murray TJ. (2006). Diagnosis and Treatment of Multiple Sclerosis. BMJ, 322 (7540):525-527.
² Tullman M. (2013). Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis. The American Journal of Managed Care. 19 (2): S15-S20.
³ National Institutes of Health-National Institute of Neurological Disorders and Stroke. (2015). Multiple Sclerosis: Hope Through Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research.
⁴ National MS Society. "Who Gets MS? - African Americans." Retrieved November 2020. nationalmssociety.org/What-is-MS/Who-Gets-MS/African-American-Resources.
⁵ Langer-Gould A, et al. Neurology. 2013;80:1734-1739; 2. Wallin MT, et al. Brain. 2012;135:1778-1785.
⁶ U.S. Food and Drug Administration. “Clinical Trials Shed Light on Minority Health.” U.S. Food and Drug Administration Website. https://wayback.archive-it.org/7993/20180908114418/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm349063.htm. Published 2018.
⁷ Genentech. “A New Perspective on Health Inequity.” https://www.gene.com/stories/a-new-perspective-on-health-inequity.

It’s undeniable that great strides have been made in advancing the science of multiple sclerosis (MS) over the past 20 years. Continued pursuit of research and discovery has revolutionized the understanding, diagnosis, and treatment of this debilitating condition that causes symptoms that may impact nearly every part of the body and mind. Despite these advancements, there is still more work to be done.

As the search for a cure continues, it’s imperative to ask the big questions: How does MS develop and progress? How can we reduce health disparities in care and treatment? How can we improve existing treatments and expedite the discovery of new ones? To continue making progress, we must stretch the boundaries of scientific understanding until we have answers and solutions to these and other important questions.

We know that MS is a leading cause of non-traumatic disability for young people.^1,2 Yet, one of the biggest challenges for neurologists is that every person’s experience with MS is unique, making it difficult to predict what symptoms will manifest, how disruptive the symptoms and relapses will be and how a person will respond to treatment.

Twenty years ago, it was widely thought that MS was mainly driven by T cells, but in the late 1990’s, a team of researchers made a groundbreaking discovery: B cells also played a key role in MS. This discovery redefined how the scientific community thought about the underlying biology of MS and the central role B cells can play. 

It was this bold thinking that led researchers at the University of California, San Francisco (UCSF) and scientists at Genentech, a member of the Roche Group, to explore whether a medication that depleted B cells would have an impact on MS. This collaboration, in turn, inspired the clinical research behind Ocrevus^® (ocrelizumab), the first and only treatment approved by the FDA for both relapsing MS (RMS) and primary progressive MS (PPMS). MS is a progressive disease from the start. An important goal of treating MS is to reduce disease progression as soon as possible to slow how quickly a person’s disability changes and prevent the long-term consequences of disease progression.³ Ocrevus is administered via infusion twice yearly, with the initial dose split into two separate infusions and given two weeks apart. As with any therapy, this treatment has side effects, which can be found in the full Prescribing Information and Medication Guide. Ocrevus is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reactions to Ocrevus. The warnings and precautions for Ocrevus are infusion reactions, and infections, which include respiratory tract infections, herpes, progressive multifocal leukoencephalopathy (PML), and hepatitis B virus (HBV) reactivation. Additional warnings are possible increased risk of immunosuppressant effects with other immunosuppressants, reduction in immunoglobulins, and malignancies.

Ensuring a Continuum of Care 
Another significant challenge facing the MS community is ensuring ongoing support and care for people living with the condition, especially throughout the COVID-19 pandemic. “We know that seeking early and appropriate care for MS is critical to slowing disability progression and achieving successful patient outcomes,” said Dr. Ashish Pradhan, Executive Director of Neuroimmunology at Genentech. “The pandemic has created additional barriers to early diagnosis and treatment, but we are committed to continuing to do everything we can to support patients and physicians at this stressful time.” Dr. Pradhan also observed that FDA's approval of a shorter infusion time for Ocrevus in December 2020 could potentially contribute to reducing some of the burden on the healthcare system in the long-term.

Being able to connect with others in the MS community is a vital part of navigating the uncertainties of living with the condition. This past April, to shine a light on the diverse MS community, Genentech hosted an #MSVisibility Virtual Concert that gathered people from across the world with different backgrounds and MS experiences and encouraged people living with MS to continue seeking appropriate support and care during the pandemic.

Continued support of the MS community through advocacy partnerships and grants over the years has played a sustained role in Genentech’s efforts to ensure people with MS receive necessary medical care and treatment. For example, Genentech partnered with an MS advocacy organization to fund a program that helps people get to and from their medical appointments. In addition, for more than 30 years, Genentech has helped more than two million people get the medicine they need through patient assistance programs like Genentech Access Solutions and the Genentech Patient Foundation.

Advancing Inclusive Research in MS 
MS has been shown to impact individuals and specific populations in markedly different ways. Those who identify as Black or of African descent and Hispanic/Latinos for example can experience more severe symptoms and faster disease progression than their Caucasian counterparts.^4,5 Unfortunately, it’s not clear exactly why, largely because of their vast underrepresentation in clinical trials (less than 5% and 1%, respectively).⁶ While there are multiple explanations for these disparities, around one-in-three minority patients don’t participate in clinical trials due to lack of trust and 52% feel that the healthcare system is not only flawed, but is actually working against them.⁷

“Increased diversity in research is paramount to ensuring that the healthcare system is serving every person living with MS and ultimately reducing health inequities while providing more tailored treatment options,” commented Dr. Pradhan. “To advance the care of undertreated and underserved people with MS, we are creating and supporting programs, grants and other initiatives focused on people of color and inclusive and minority research to better understand how MS presents itself and develops in different patient populations. We want to make sure that all generations of people living with MS are equally represented in clinical research and have access to the treatments that will work best for them.”

Refining Existing Approaches and Leading Treatment Innovation
For decades, Genentech and Roche have been conducting neuroscience research and clinical trials to make forward progress in understanding and treating a variety of neurological conditions, including MS. While the treatment landscape for MS has evolved significantly over the past two decades, continued investment in research and development is critical. Continuing to review and refine existing treatment approaches may improve patient outcomes and discovering new treatment approaches may play an important role in advancing the treatment paradigm.

Dr. Pradhan added, “as the scientific community continues to think boldly, and re-imagine treatment and care for MS, we hope to continue to improve our understanding of the condition for all people with the disease, and advance treatment options. Pushing boundaries means refusing to stop until everyone living with MS can be treated effectively and a cure is found. This sentiment reminds me of a Ralph Waldo Emerson quote, ‘Don’t follow where the path may lead. Go instead where there is no path and leave a trail.’ That’s what we are trying to do at Genentech.”

To learn more, please visit Ocrevus.com.

Indications and Important Safety Information
OCREVUS is indicated for the treatment of:

• Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
• Primary progressive MS, in adults. 

Contraindications
OCREVUS is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening infusion reaction to OCREVUS.

Warnings and Precautions

Infusion Reactions  

OCREVUS can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in OCREVUS-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34-40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of OCREVUS-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.  

Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered. For life-threatening infusion reactions, immediately and permanently stop OCREVUS and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections

A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more infections compared to 68% of patients on placebo. OCREVUS increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. OCREVUS was not associated with an increased risk of serious infections in MS patients. Delay OCREVUS administration in patients with an active infection until the infection is resolved.

Respiratory Tract Infections

A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-treated patients than in the patients on placebo (2.7% vs 0.8%).

Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving OCREVUS. Serious herpes virus infections may occur at any time during treatment with OCREVUS. Some cases were life-threatening. 

If serious herpes infections occur, OCREVUS should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered.

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in OCREVUS clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes (per USPI).

Hepatitis B Virus (HBV) Reactivation

Hepatitis B reactivation has been reported in MS patients treated with OCREVUS in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with OCREVUS. Do not administer OCREVUS to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

When initiating OCREVUS after an immunosuppressive therapy or initiating an immunosuppressive therapy after OCREVUS, consider the potential for increased immunosuppressive effect. OCREVUS has not been studied in combination with other MS therapies.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of OCREVUS for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of OCREVUS for non-live vaccines. OCREVUS may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines following OCREVUS therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with OCREVUS During Pregnancy

In infants of mothers exposed to OCREVUS during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Malignancies  

An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.

Use in Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to OCREVUS during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-872-4370 or visiting www.ocrevuspregnancyregistry.com.

There are no adequate data on the developmental risk associated with use of OCREVUS in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to OCREVUS. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. OCREVUS is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. 

Lactation 

There are no data on the presence of ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OCREVUS and any potential adverse effects on the breastfed infant from OCREVUS or from the underlying maternal condition.

Females and Males of Reproductive Potential

Women of childbearing potential should use effective contraception while receiving OCREVUS and for 6 months after the last infusion of OCREVUS.

Most Common Adverse Reactions

RMS: The most common adverse reactions in RMS trials (incidence ≥10% and >REBIF) were upper respiratory tract infections (40%) and infusion reactions (34%).
 

PPMS: The most common adverse reactions in PPMS trials (incidence ≥10% and >placebo) were upper respiratory tract infections (49%), infusion reactions (40%), skin infections (14%), and lower respiratory tract infections (10%).

For additional safety information, please see the full Prescribing Information and Medication Guide.

¹ Murray TJ. (2006). Diagnosis and Treatment of Multiple Sclerosis. BMJ, 322 (7540):525-527.
² Tullman M. (2013). Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis. The American Journal of Managed Care. 19 (2): S15-S20.
³ National Institutes of Health-National Institute of Neurological Disorders and Stroke. (2015). Multiple Sclerosis: Hope Through Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research.
⁴ National MS Society. "Who Gets MS? - African Americans." Retrieved November 2020. nationalmssociety.org/What-is-MS/Who-Gets-MS/African-American-Resources.
⁵ Langer-Gould A, et al. Neurology. 2013;80:1734-1739; 2. Wallin MT, et al. Brain. 2012;135:1778-1785.
⁶ U.S. Food and Drug Administration. “Clinical Trials Shed Light on Minority Health.” U.S. Food and Drug Administration Website. https://wayback.archive-it.org/7993/20180908114418/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm349063.htm. Published 2018.
⁷ Genentech. “A New Perspective on Health Inequity.” https://www.gene.com/stories/a-new-perspective-on-health-inequity.

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

Clinicians are prescribing clarithromycin at high rates for Helicobacter pylori infections, despite increasing resistance to this antibiotic, researchers say.

In an analysis of 1 million U.S. prescriptions for H. pylori infections, 80% contained clarithromycin, said Carol Rockett, PharmD, associate vice president of RedHill Biopharma in Raleigh, N.C.

Dr. Rockett presented the findings at the annual meeting of the American College of Gastroenterology.

“Multiple talks [at the meeting] have suggested that the use of clarithromycin in H. pylori is obsolete,” she told this news organization. “Clarithromycin is particularly ineffective in people with a genetic variant that causes rapid metabolism.”

According to the 2017 ACG clinical guideline for treating H. pylori, patients diagnosed with this infection should be asked about their previous antibiotic exposure prior to treatment.

Additionally, clinicians should prescribe clarithromycin triple therapy with a proton pump inhibitor (PPI) and amoxicillin or metronidazole as a first-line treatment only in “regions where H. pylori clarithromycin resistance is known to be less than 15%” and in patients with no previous history of macrolide exposure.

The guideline puts bismuth quadruple therapy, consisting of a PPI, bismuth, tetracycline, and a nitroimidazole, at the top of its list of six alternative first-line therapies. However, three of the six alternatives include clarithromycin.
 

ERADICATE Hp and ERADICATE Hp2

To understand how U.S. physicians are treating patients with H. pylori, Dr. Rockett’s colleagues analyzed data from two phase 3 clinical trials of RedHill’s RHB-105 (Talicia): ERADICATE Hp and ERADICATE Hp2.

RHB-105 is an all-in‐one combination of omeprazole (40 mg), amoxicillin (1,000 mg), and rifabutin (50 mg) that the Food and Drug Administration approved for treatment of H pylori in 2019.

The researchers followed 38 subjects from ERADICATE Hp who remained positive for H. pylori after the study’s completion. A total of 33 had received a placebo in that trial, while the other 5 had received RHB-105.

The researchers obtained data on 31 of these patients. The overall cure rate was 61.3%. Of the 31 patients, 27 received a regimen including clarithromycin. Their cure rate was 59.3%.

Turning to ERADICATE Hp2, the researchers obtained data on 94 patients whose H. pylori infections persisted after the trial. Of those, 67 had received an active comparator (amoxicillin 250 mg and omeprazole 10 mg) and 27 had received RHB-105.

The overall cure rate was 56.2%. For the 48 subjects who received therapies including clarithromycin, the cure rate was 60.4%. For the 22 subjects who received a bismuth-based quadruple regimen, the cure rate was 45.4%.

In another analysis, the researchers crunched 12 months of numbers from IQVIA PharMetrics Plus medical and prescription claim database of over 1 million prescriptions for H. pylori. They found that 80% of the prescriptions made by gastroenterologists were for regimens containing clarithromycin. That proportion increased to 84% for physician assistants and internists, 85% for nurse practitioners, 86% for family practitioners, and 89% for general practitioners.

Finally, the researchers also analyzed patients for CYP2C19 gene status. They tested 65 subjects who received RHB-105 in ERADICATE Hp and all 445 subjects in ERADICATE Hp2. They found that 58.5% in ERADICATE Hp and 48.6% in ERADICATE Hp2 were normal metabolizers.

In 20 normal metabolizers who received clarithromycin, the drug eradicated the infection in 16 (80%). Out of 11 rapid metabolizers, clarithromycin eradicated the bacterium in 2 (18.2%). The difference was statistically significant (P = .0017).

“With clarithromycin, you can see that the efficacy is reduced in those patients who are rapid metabolizers,” Dr. Rockett said. “We didn’t see that with rifabutin [one of the drugs in RHB-105].”

Jared Magee, DO, MPH, a gastroenterology fellow at the Walter Reed National Military Medical Center in Bethesda, Md., said in treating H. pylori infections, he checks the patients’ medical records to see what antibiotics they have received in the past and generally begins treatment with the bismuth quadruple therapy.

“There is education needed to get the data out there that clarithromycin-based therapies may not be the right choice for patients,” he said. “There is a subset who will do well with it, but I think where we’re at now, with the frequency of macrolide prescriptions for other conditions, that clarithromycin is going to be a difficult therapy for a lot of people.”

Clinicians who are not gastroenterologists may not be aware of the guideline promulgated by the ACG, he pointed out.

Dr. Rockett is an employee of RedHill Biopharma. Dr. Magee has disclosed no relevant financial relationships. The study was funded by RedHill Biopharma.

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

Clinicians are prescribing clarithromycin at high rates for Helicobacter pylori infections, despite increasing resistance to this antibiotic, researchers say.

In an analysis of 1 million U.S. prescriptions for H. pylori infections, 80% contained clarithromycin, said Carol Rockett, PharmD, associate vice president of RedHill Biopharma in Raleigh, N.C.

Dr. Rockett presented the findings at the annual meeting of the American College of Gastroenterology.

“Multiple talks [at the meeting] have suggested that the use of clarithromycin in H. pylori is obsolete,” she told this news organization. “Clarithromycin is particularly ineffective in people with a genetic variant that causes rapid metabolism.”

According to the 2017 ACG clinical guideline for treating H. pylori, patients diagnosed with this infection should be asked about their previous antibiotic exposure prior to treatment.

Additionally, clinicians should prescribe clarithromycin triple therapy with a proton pump inhibitor (PPI) and amoxicillin or metronidazole as a first-line treatment only in “regions where H. pylori clarithromycin resistance is known to be less than 15%” and in patients with no previous history of macrolide exposure.

The guideline puts bismuth quadruple therapy, consisting of a PPI, bismuth, tetracycline, and a nitroimidazole, at the top of its list of six alternative first-line therapies. However, three of the six alternatives include clarithromycin.
 

ERADICATE Hp and ERADICATE Hp2

To understand how U.S. physicians are treating patients with H. pylori, Dr. Rockett’s colleagues analyzed data from two phase 3 clinical trials of RedHill’s RHB-105 (Talicia): ERADICATE Hp and ERADICATE Hp2.

RHB-105 is an all-in‐one combination of omeprazole (40 mg), amoxicillin (1,000 mg), and rifabutin (50 mg) that the Food and Drug Administration approved for treatment of H pylori in 2019.

The researchers followed 38 subjects from ERADICATE Hp who remained positive for H. pylori after the study’s completion. A total of 33 had received a placebo in that trial, while the other 5 had received RHB-105.

The researchers obtained data on 31 of these patients. The overall cure rate was 61.3%. Of the 31 patients, 27 received a regimen including clarithromycin. Their cure rate was 59.3%.

Turning to ERADICATE Hp2, the researchers obtained data on 94 patients whose H. pylori infections persisted after the trial. Of those, 67 had received an active comparator (amoxicillin 250 mg and omeprazole 10 mg) and 27 had received RHB-105.

The overall cure rate was 56.2%. For the 48 subjects who received therapies including clarithromycin, the cure rate was 60.4%. For the 22 subjects who received a bismuth-based quadruple regimen, the cure rate was 45.4%.

In another analysis, the researchers crunched 12 months of numbers from IQVIA PharMetrics Plus medical and prescription claim database of over 1 million prescriptions for H. pylori. They found that 80% of the prescriptions made by gastroenterologists were for regimens containing clarithromycin. That proportion increased to 84% for physician assistants and internists, 85% for nurse practitioners, 86% for family practitioners, and 89% for general practitioners.

Finally, the researchers also analyzed patients for CYP2C19 gene status. They tested 65 subjects who received RHB-105 in ERADICATE Hp and all 445 subjects in ERADICATE Hp2. They found that 58.5% in ERADICATE Hp and 48.6% in ERADICATE Hp2 were normal metabolizers.

In 20 normal metabolizers who received clarithromycin, the drug eradicated the infection in 16 (80%). Out of 11 rapid metabolizers, clarithromycin eradicated the bacterium in 2 (18.2%). The difference was statistically significant (P = .0017).

“With clarithromycin, you can see that the efficacy is reduced in those patients who are rapid metabolizers,” Dr. Rockett said. “We didn’t see that with rifabutin [one of the drugs in RHB-105].”

Jared Magee, DO, MPH, a gastroenterology fellow at the Walter Reed National Military Medical Center in Bethesda, Md., said in treating H. pylori infections, he checks the patients’ medical records to see what antibiotics they have received in the past and generally begins treatment with the bismuth quadruple therapy.

“There is education needed to get the data out there that clarithromycin-based therapies may not be the right choice for patients,” he said. “There is a subset who will do well with it, but I think where we’re at now, with the frequency of macrolide prescriptions for other conditions, that clarithromycin is going to be a difficult therapy for a lot of people.”

Clinicians who are not gastroenterologists may not be aware of the guideline promulgated by the ACG, he pointed out.

Dr. Rockett is an employee of RedHill Biopharma. Dr. Magee has disclosed no relevant financial relationships. The study was funded by RedHill Biopharma.

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

Clinicians are prescribing clarithromycin at high rates for Helicobacter pylori infections, despite increasing resistance to this antibiotic, researchers say.

In an analysis of 1 million U.S. prescriptions for H. pylori infections, 80% contained clarithromycin, said Carol Rockett, PharmD, associate vice president of RedHill Biopharma in Raleigh, N.C.

Dr. Rockett presented the findings at the annual meeting of the American College of Gastroenterology.

“Multiple talks [at the meeting] have suggested that the use of clarithromycin in H. pylori is obsolete,” she told this news organization. “Clarithromycin is particularly ineffective in people with a genetic variant that causes rapid metabolism.”

According to the 2017 ACG clinical guideline for treating H. pylori, patients diagnosed with this infection should be asked about their previous antibiotic exposure prior to treatment.

Additionally, clinicians should prescribe clarithromycin triple therapy with a proton pump inhibitor (PPI) and amoxicillin or metronidazole as a first-line treatment only in “regions where H. pylori clarithromycin resistance is known to be less than 15%” and in patients with no previous history of macrolide exposure.

The guideline puts bismuth quadruple therapy, consisting of a PPI, bismuth, tetracycline, and a nitroimidazole, at the top of its list of six alternative first-line therapies. However, three of the six alternatives include clarithromycin.
 

ERADICATE Hp and ERADICATE Hp2

To understand how U.S. physicians are treating patients with H. pylori, Dr. Rockett’s colleagues analyzed data from two phase 3 clinical trials of RedHill’s RHB-105 (Talicia): ERADICATE Hp and ERADICATE Hp2.

RHB-105 is an all-in‐one combination of omeprazole (40 mg), amoxicillin (1,000 mg), and rifabutin (50 mg) that the Food and Drug Administration approved for treatment of H pylori in 2019.

The researchers followed 38 subjects from ERADICATE Hp who remained positive for H. pylori after the study’s completion. A total of 33 had received a placebo in that trial, while the other 5 had received RHB-105.

The researchers obtained data on 31 of these patients. The overall cure rate was 61.3%. Of the 31 patients, 27 received a regimen including clarithromycin. Their cure rate was 59.3%.

Turning to ERADICATE Hp2, the researchers obtained data on 94 patients whose H. pylori infections persisted after the trial. Of those, 67 had received an active comparator (amoxicillin 250 mg and omeprazole 10 mg) and 27 had received RHB-105.

The overall cure rate was 56.2%. For the 48 subjects who received therapies including clarithromycin, the cure rate was 60.4%. For the 22 subjects who received a bismuth-based quadruple regimen, the cure rate was 45.4%.

In another analysis, the researchers crunched 12 months of numbers from IQVIA PharMetrics Plus medical and prescription claim database of over 1 million prescriptions for H. pylori. They found that 80% of the prescriptions made by gastroenterologists were for regimens containing clarithromycin. That proportion increased to 84% for physician assistants and internists, 85% for nurse practitioners, 86% for family practitioners, and 89% for general practitioners.

Finally, the researchers also analyzed patients for CYP2C19 gene status. They tested 65 subjects who received RHB-105 in ERADICATE Hp and all 445 subjects in ERADICATE Hp2. They found that 58.5% in ERADICATE Hp and 48.6% in ERADICATE Hp2 were normal metabolizers.

In 20 normal metabolizers who received clarithromycin, the drug eradicated the infection in 16 (80%). Out of 11 rapid metabolizers, clarithromycin eradicated the bacterium in 2 (18.2%). The difference was statistically significant (P = .0017).

“With clarithromycin, you can see that the efficacy is reduced in those patients who are rapid metabolizers,” Dr. Rockett said. “We didn’t see that with rifabutin [one of the drugs in RHB-105].”

Jared Magee, DO, MPH, a gastroenterology fellow at the Walter Reed National Military Medical Center in Bethesda, Md., said in treating H. pylori infections, he checks the patients’ medical records to see what antibiotics they have received in the past and generally begins treatment with the bismuth quadruple therapy.

“There is education needed to get the data out there that clarithromycin-based therapies may not be the right choice for patients,” he said. “There is a subset who will do well with it, but I think where we’re at now, with the frequency of macrolide prescriptions for other conditions, that clarithromycin is going to be a difficult therapy for a lot of people.”

Clinicians who are not gastroenterologists may not be aware of the guideline promulgated by the ACG, he pointed out.

Dr. Rockett is an employee of RedHill Biopharma. Dr. Magee has disclosed no relevant financial relationships. The study was funded by RedHill Biopharma.

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

Patients with multiple sclerosis (MS) may be more likely to develop psoriasis if they take certain B cell-depleting therapies, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.

“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”

The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).

The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.

The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).

Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.

The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.

Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.

As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.

Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”

No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.

Patients with multiple sclerosis (MS) may be more likely to develop psoriasis if they take certain B cell-depleting therapies, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.

“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”

The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).

The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.

The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).

Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.

The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.

Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.

As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.

Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”

No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.

Patients with multiple sclerosis (MS) may be more likely to develop psoriasis if they take certain B cell-depleting therapies, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.

“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”

The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).

The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.

The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).

Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.

The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.

Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.

As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.

Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”

No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.

In this supplement to Current Psychiatry, Greg Mattingly, MD and Manish K. Jha, MBBS review dilemmas and treatment options for patients with tardive dyskinesia.

Click here to read the supplement and earn free CME/CE credits.


 

In this supplement to Current Psychiatry, Greg Mattingly, MD and Manish K. Jha, MBBS review dilemmas and treatment options for patients with tardive dyskinesia.

Click here to read the supplement and earn free CME/CE credits.


 

In this supplement to Current Psychiatry, Greg Mattingly, MD and Manish K. Jha, MBBS review dilemmas and treatment options for patients with tardive dyskinesia.

Click here to read the supplement and earn free CME/CE credits.


 

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

When managing seizures, physicians have multiple treatment choices developed over the past half century. Partial-onset seizures, or focal seizures, represent the majority of cases. Neurologists and primary care providers are tasked with choosing the first-, second-, or third-line option for monotherapy, and determining when treatment-refractory cases require adjunct treatment. 

This supplement reviews Eslicarbazepine Acetate and its effectiveness as a first-line or later adjunctive therapy in patients with partial-onset seizures.
 

Click here to read more

When managing seizures, physicians have multiple treatment choices developed over the past half century. Partial-onset seizures, or focal seizures, represent the majority of cases. Neurologists and primary care providers are tasked with choosing the first-, second-, or third-line option for monotherapy, and determining when treatment-refractory cases require adjunct treatment. 

This supplement reviews Eslicarbazepine Acetate and its effectiveness as a first-line or later adjunctive therapy in patients with partial-onset seizures.
 

Click here to read more

When managing seizures, physicians have multiple treatment choices developed over the past half century. Partial-onset seizures, or focal seizures, represent the majority of cases. Neurologists and primary care providers are tasked with choosing the first-, second-, or third-line option for monotherapy, and determining when treatment-refractory cases require adjunct treatment. 

This supplement reviews Eslicarbazepine Acetate and its effectiveness as a first-line or later adjunctive therapy in patients with partial-onset seizures.
 

Click here to read more

Cheryl K. Lee, MD, an Assistant Professor Of Medicine at Northwestern Feinberg School of Medicine, practices internal medicine and pediatrics at Northwestern Memorial and the Ann & Robert H. Lurie Children's Hospital, both in Chicago, IL. She also serves on the Northwestern Medicine Covid Quality Committee and as core clinical faculty in the Internal Medicine Residency.  

Dr. Lee reported no disclosures.

You have been treating COVID-19 patients since before the US Food and Drug Administration (FDA) granted emergency authorization to 3 pharma vaccine producers. But now you have patients, on oxygen or under observation, who have foregone vaccination. What do you think about that?

This question raises a good point that is often missed: how the unvaccinated are often portrayed. The reasons these patients remain unvaccinated are not necessarily uniform.

What we know based on attitude surveys done by the Kaiser Family Foundation¹ is that people are vaccine hesitant for varied reasons. And this finding isn’t unique. The pediatric literature shows that those who are opposed to childhood vaccination do not share the same motivations.² Yes, some are strident about their beliefs against vaccination, usually in concert with popularized myths. Many unvaccinated people are hesitant based on misconceptions, do not have access to a clinician who can answer their questions, can’t afford to lose a day of work due to the vaccine’s expected side effects, or understandably mistrust the healthcare community based on personal or historical context.

What do the unvaccinated have in common? Education levels, income levels?

We know from surveys³ that generally, more men than women are hesitant. Those who are uninsured or underinsured⁴ and those of lower socioeconomic status are more hesitant than their counterparts. It's changing a bit, but those who are in minority communities, Black and Latinx communities, are more likely to be unvaccinated compared to other groups. Even in Chicago, where we have a relatively good vaccination rate (59%),⁵ Black and Latinx communities are under vaccinated as compared to those who are White or Asian. The reasons for this are complex and include historical disinvestment in communities and decreased access to medical care. Some wonderful agencies are pairing up with community leaders in target neighborhoods to address this equity gap.

What do you say to these patients, if anything, about their status?

It’s not what you might expect. At first, I listen. I find that most are well-intentioned people trying to make the right decision for themselves and their family. It is, therefore, helpful to hear what their motivations and fears are first, before delving into facts. Furthermore, although facts are wonderful and necessary, what is more persuasive is a personal anecdote. I will tell folks my personal story about deciding to be vaccinated. I talk about how I found accurate information about the vaccine and what a relief it was afterwards to know that I would be safe, especially as a mom. I even talk about feeling tired and achy after the second shot, which means that the vaccine is working. I joke that it is the only time I’ve felt so relieved to feel sick. Last, I often say that it’s okay to feel scared or apprehensive, and that they deserve to get the best information. What’s important is that these conversations feel genuine.

Can you share an anecdote or two?

A few months ago, I took care of an unvaccinated gentleman who was in the hospital for a chronic medical condition. Before this hospitalization, his personal physicians had tried to convince him to get the vaccine over a period of several months.

It would have been easy to assume that he would remain unvaccinated and that I should put my energy into convincing someone else. However, I found him surprisingly open to discussion, and we were able to have many conversations about what he'd heard from nonmedical sources. We bonded over the sheer volume of available information and how difficult it is to know what is true. We then walked through what was truth vs fiction, and I tailored the discussion to how the vaccine could specifically improve his quality of life and his family's. He confided that what made his decision more difficult was the fact that he hadn’t met anyone who had gotten the vaccine among his friends and family. He ultimately did decide to get vaccinated, along with a family member. We made the appointment for the week after he was discharged. What a feeling it was to get a text message from his clinic physician saying that he got his first shot and that it went great!

I wasn’t the only physician who had spoken to this patient about getting vaccinated; others had done the same before he came to the hospital. It is a good reminder that each conversation can act like a gentle nudge in the right direction.

In terms of the data on the unvaccinated–reasons they stay away, what their backgrounds are and so forth–how close do those data play out in real life?

It is not advisable to assume why someone would be unvaccinated based on first impressions. I find the reasons are highly specific to that individual, ranging from false impressions about fertility to concerns about missing work. In my experience, several patients simply wanted to get more facts from a healthcare worker directly before signing up. Pregnancy is particularly important to talk about, considering how devastating the Delta variant has been to this group of women. One gentleman that I spoke to was worried about affecting his wife’s pregnancy with the vaccine. We know now that vaccines are safe and prevent pregnant patients from getting seriously ill and dying, but that knowledge isn’t widely known to the public. So many kind and well-meaning people have foregone vaccination because they're concerned about doing anything to upset the pregnancy.

How long, generally, does it take for unvaccinated patients to discuss the reasons for their choice?

It takes time, and that's a real barrier for many healthcare professionals, especially in a clinic setting where the luxury of extra time is nonexistent. How much time differs for everyone, and usually a change of heart takes more than one conversation.

Truly, the first conversation is just to listen, to understand their hesitation, and to develop trust. For anyone to really hear what I have to say, they must trust that what I'm saying is solely motivated by caring about what happens to them and their family.

One gentleman said something pointed during our first conversation: Thank you for listening. When I tell people I am not vaccinated I can feel them judging me, that they've already decided what to think of me.

I always tell people that they have good questions because they do. I respect the fact that they're feeling open enough to share what they're hearing or what they're afraid of. It's a privilege for me to be involved in that conversation.

What advice would you give other hospitalists in terms of treating and counseling patients who are unvaccinated?

Every hospitalization, whether it’s COVID-related or not, is an opportunity to speak with those who are still unvaccinated. Every encounter can be used to further the conversation about vaccines, by increasing their trust in the healthcare community, answering their questions, and providing facts in place of confusion. Using those opportunities is the best way to get us out of this pandemic.

That said, it's been a long two years, so it's okay if physicians don't have the emotional bandwidth or the time to have these discussions. Maybe save that conversation for another day. But for some providers, perhaps knowing that those who are unvaccinated can change and that anxiety could be preventing some from getting their shot will motivate them to start these conversations with their patients.

Cheryl K. Lee, MD, an Assistant Professor Of Medicine at Northwestern Feinberg School of Medicine, practices internal medicine and pediatrics at Northwestern Memorial and the Ann & Robert H. Lurie Children's Hospital, both in Chicago, IL. She also serves on the Northwestern Medicine Covid Quality Committee and as core clinical faculty in the Internal Medicine Residency.  

Dr. Lee reported no disclosures.

You have been treating COVID-19 patients since before the US Food and Drug Administration (FDA) granted emergency authorization to 3 pharma vaccine producers. But now you have patients, on oxygen or under observation, who have foregone vaccination. What do you think about that?

This question raises a good point that is often missed: how the unvaccinated are often portrayed. The reasons these patients remain unvaccinated are not necessarily uniform.

What we know based on attitude surveys done by the Kaiser Family Foundation¹ is that people are vaccine hesitant for varied reasons. And this finding isn’t unique. The pediatric literature shows that those who are opposed to childhood vaccination do not share the same motivations.² Yes, some are strident about their beliefs against vaccination, usually in concert with popularized myths. Many unvaccinated people are hesitant based on misconceptions, do not have access to a clinician who can answer their questions, can’t afford to lose a day of work due to the vaccine’s expected side effects, or understandably mistrust the healthcare community based on personal or historical context.

What do the unvaccinated have in common? Education levels, income levels?

We know from surveys³ that generally, more men than women are hesitant. Those who are uninsured or underinsured⁴ and those of lower socioeconomic status are more hesitant than their counterparts. It's changing a bit, but those who are in minority communities, Black and Latinx communities, are more likely to be unvaccinated compared to other groups. Even in Chicago, where we have a relatively good vaccination rate (59%),⁵ Black and Latinx communities are under vaccinated as compared to those who are White or Asian. The reasons for this are complex and include historical disinvestment in communities and decreased access to medical care. Some wonderful agencies are pairing up with community leaders in target neighborhoods to address this equity gap.

What do you say to these patients, if anything, about their status?

It’s not what you might expect. At first, I listen. I find that most are well-intentioned people trying to make the right decision for themselves and their family. It is, therefore, helpful to hear what their motivations and fears are first, before delving into facts. Furthermore, although facts are wonderful and necessary, what is more persuasive is a personal anecdote. I will tell folks my personal story about deciding to be vaccinated. I talk about how I found accurate information about the vaccine and what a relief it was afterwards to know that I would be safe, especially as a mom. I even talk about feeling tired and achy after the second shot, which means that the vaccine is working. I joke that it is the only time I’ve felt so relieved to feel sick. Last, I often say that it’s okay to feel scared or apprehensive, and that they deserve to get the best information. What’s important is that these conversations feel genuine.

Can you share an anecdote or two?

A few months ago, I took care of an unvaccinated gentleman who was in the hospital for a chronic medical condition. Before this hospitalization, his personal physicians had tried to convince him to get the vaccine over a period of several months.

It would have been easy to assume that he would remain unvaccinated and that I should put my energy into convincing someone else. However, I found him surprisingly open to discussion, and we were able to have many conversations about what he'd heard from nonmedical sources. We bonded over the sheer volume of available information and how difficult it is to know what is true. We then walked through what was truth vs fiction, and I tailored the discussion to how the vaccine could specifically improve his quality of life and his family's. He confided that what made his decision more difficult was the fact that he hadn’t met anyone who had gotten the vaccine among his friends and family. He ultimately did decide to get vaccinated, along with a family member. We made the appointment for the week after he was discharged. What a feeling it was to get a text message from his clinic physician saying that he got his first shot and that it went great!

I wasn’t the only physician who had spoken to this patient about getting vaccinated; others had done the same before he came to the hospital. It is a good reminder that each conversation can act like a gentle nudge in the right direction.

In terms of the data on the unvaccinated–reasons they stay away, what their backgrounds are and so forth–how close do those data play out in real life?

It is not advisable to assume why someone would be unvaccinated based on first impressions. I find the reasons are highly specific to that individual, ranging from false impressions about fertility to concerns about missing work. In my experience, several patients simply wanted to get more facts from a healthcare worker directly before signing up. Pregnancy is particularly important to talk about, considering how devastating the Delta variant has been to this group of women. One gentleman that I spoke to was worried about affecting his wife’s pregnancy with the vaccine. We know now that vaccines are safe and prevent pregnant patients from getting seriously ill and dying, but that knowledge isn’t widely known to the public. So many kind and well-meaning people have foregone vaccination because they're concerned about doing anything to upset the pregnancy.

How long, generally, does it take for unvaccinated patients to discuss the reasons for their choice?

It takes time, and that's a real barrier for many healthcare professionals, especially in a clinic setting where the luxury of extra time is nonexistent. How much time differs for everyone, and usually a change of heart takes more than one conversation.

Truly, the first conversation is just to listen, to understand their hesitation, and to develop trust. For anyone to really hear what I have to say, they must trust that what I'm saying is solely motivated by caring about what happens to them and their family.

One gentleman said something pointed during our first conversation: Thank you for listening. When I tell people I am not vaccinated I can feel them judging me, that they've already decided what to think of me.

I always tell people that they have good questions because they do. I respect the fact that they're feeling open enough to share what they're hearing or what they're afraid of. It's a privilege for me to be involved in that conversation.

What advice would you give other hospitalists in terms of treating and counseling patients who are unvaccinated?

Every hospitalization, whether it’s COVID-related or not, is an opportunity to speak with those who are still unvaccinated. Every encounter can be used to further the conversation about vaccines, by increasing their trust in the healthcare community, answering their questions, and providing facts in place of confusion. Using those opportunities is the best way to get us out of this pandemic.

That said, it's been a long two years, so it's okay if physicians don't have the emotional bandwidth or the time to have these discussions. Maybe save that conversation for another day. But for some providers, perhaps knowing that those who are unvaccinated can change and that anxiety could be preventing some from getting their shot will motivate them to start these conversations with their patients.

Cheryl K. Lee, MD, an Assistant Professor Of Medicine at Northwestern Feinberg School of Medicine, practices internal medicine and pediatrics at Northwestern Memorial and the Ann & Robert H. Lurie Children's Hospital, both in Chicago, IL. She also serves on the Northwestern Medicine Covid Quality Committee and as core clinical faculty in the Internal Medicine Residency.  

Dr. Lee reported no disclosures.

You have been treating COVID-19 patients since before the US Food and Drug Administration (FDA) granted emergency authorization to 3 pharma vaccine producers. But now you have patients, on oxygen or under observation, who have foregone vaccination. What do you think about that?

This question raises a good point that is often missed: how the unvaccinated are often portrayed. The reasons these patients remain unvaccinated are not necessarily uniform.

What we know based on attitude surveys done by the Kaiser Family Foundation¹ is that people are vaccine hesitant for varied reasons. And this finding isn’t unique. The pediatric literature shows that those who are opposed to childhood vaccination do not share the same motivations.² Yes, some are strident about their beliefs against vaccination, usually in concert with popularized myths. Many unvaccinated people are hesitant based on misconceptions, do not have access to a clinician who can answer their questions, can’t afford to lose a day of work due to the vaccine’s expected side effects, or understandably mistrust the healthcare community based on personal or historical context.

What do the unvaccinated have in common? Education levels, income levels?

We know from surveys³ that generally, more men than women are hesitant. Those who are uninsured or underinsured⁴ and those of lower socioeconomic status are more hesitant than their counterparts. It's changing a bit, but those who are in minority communities, Black and Latinx communities, are more likely to be unvaccinated compared to other groups. Even in Chicago, where we have a relatively good vaccination rate (59%),⁵ Black and Latinx communities are under vaccinated as compared to those who are White or Asian. The reasons for this are complex and include historical disinvestment in communities and decreased access to medical care. Some wonderful agencies are pairing up with community leaders in target neighborhoods to address this equity gap.

What do you say to these patients, if anything, about their status?

It’s not what you might expect. At first, I listen. I find that most are well-intentioned people trying to make the right decision for themselves and their family. It is, therefore, helpful to hear what their motivations and fears are first, before delving into facts. Furthermore, although facts are wonderful and necessary, what is more persuasive is a personal anecdote. I will tell folks my personal story about deciding to be vaccinated. I talk about how I found accurate information about the vaccine and what a relief it was afterwards to know that I would be safe, especially as a mom. I even talk about feeling tired and achy after the second shot, which means that the vaccine is working. I joke that it is the only time I’ve felt so relieved to feel sick. Last, I often say that it’s okay to feel scared or apprehensive, and that they deserve to get the best information. What’s important is that these conversations feel genuine.

Can you share an anecdote or two?

A few months ago, I took care of an unvaccinated gentleman who was in the hospital for a chronic medical condition. Before this hospitalization, his personal physicians had tried to convince him to get the vaccine over a period of several months.

It would have been easy to assume that he would remain unvaccinated and that I should put my energy into convincing someone else. However, I found him surprisingly open to discussion, and we were able to have many conversations about what he'd heard from nonmedical sources. We bonded over the sheer volume of available information and how difficult it is to know what is true. We then walked through what was truth vs fiction, and I tailored the discussion to how the vaccine could specifically improve his quality of life and his family's. He confided that what made his decision more difficult was the fact that he hadn’t met anyone who had gotten the vaccine among his friends and family. He ultimately did decide to get vaccinated, along with a family member. We made the appointment for the week after he was discharged. What a feeling it was to get a text message from his clinic physician saying that he got his first shot and that it went great!

I wasn’t the only physician who had spoken to this patient about getting vaccinated; others had done the same before he came to the hospital. It is a good reminder that each conversation can act like a gentle nudge in the right direction.

In terms of the data on the unvaccinated–reasons they stay away, what their backgrounds are and so forth–how close do those data play out in real life?

It is not advisable to assume why someone would be unvaccinated based on first impressions. I find the reasons are highly specific to that individual, ranging from false impressions about fertility to concerns about missing work. In my experience, several patients simply wanted to get more facts from a healthcare worker directly before signing up. Pregnancy is particularly important to talk about, considering how devastating the Delta variant has been to this group of women. One gentleman that I spoke to was worried about affecting his wife’s pregnancy with the vaccine. We know now that vaccines are safe and prevent pregnant patients from getting seriously ill and dying, but that knowledge isn’t widely known to the public. So many kind and well-meaning people have foregone vaccination because they're concerned about doing anything to upset the pregnancy.

How long, generally, does it take for unvaccinated patients to discuss the reasons for their choice?

It takes time, and that's a real barrier for many healthcare professionals, especially in a clinic setting where the luxury of extra time is nonexistent. How much time differs for everyone, and usually a change of heart takes more than one conversation.

Truly, the first conversation is just to listen, to understand their hesitation, and to develop trust. For anyone to really hear what I have to say, they must trust that what I'm saying is solely motivated by caring about what happens to them and their family.

One gentleman said something pointed during our first conversation: Thank you for listening. When I tell people I am not vaccinated I can feel them judging me, that they've already decided what to think of me.

I always tell people that they have good questions because they do. I respect the fact that they're feeling open enough to share what they're hearing or what they're afraid of. It's a privilege for me to be involved in that conversation.

What advice would you give other hospitalists in terms of treating and counseling patients who are unvaccinated?

Every hospitalization, whether it’s COVID-related or not, is an opportunity to speak with those who are still unvaccinated. Every encounter can be used to further the conversation about vaccines, by increasing their trust in the healthcare community, answering their questions, and providing facts in place of confusion. Using those opportunities is the best way to get us out of this pandemic.

That said, it's been a long two years, so it's okay if physicians don't have the emotional bandwidth or the time to have these discussions. Maybe save that conversation for another day. But for some providers, perhaps knowing that those who are unvaccinated can change and that anxiety could be preventing some from getting their shot will motivate them to start these conversations with their patients.