Lupus & Connective Tissue Diseases

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

[email protected]

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

[email protected]

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

[email protected]

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Withholding mycophenolate around the time of vaccination against SARS-CoV-2 proved safe and augmented the humoral response to vaccination among a group of patients at one center who were taking the immunosuppressive drug for a variety of rheumatic and musculoskeletal diseases (RMDs).

Previous studies have shown that use of mycophenolate attenuates the humoral response to SARS-CoV-2 vaccination, and the most up-to-date recommendations from the American College of Rheumatology on SARS-CoV-2 vaccination in patients with RMDs advise that mycophenolate should be withheld for a week after receiving the vaccine.

To understand better how withholding mycophenolate would affect immune response to SARS-CoV-2 vaccination, rheumatology fellow Caoilfhionn M. Connolly, MD, and coauthors at Johns Hopkins University, Baltimore, described in their report – published online Sept. 23, 2021, in Annals of the Rheumatic Diseases – how they compared the immune responses to vaccination in 24 patients who withheld mycophenolate and 171 patients who did not stop taking it. All but 1 of the 24 patients who withheld mycophenolate were female, with a median age of 51 years, and they had mostly systemic lupus erythematosus (6 patients), myositis (5), scleroderma (4), or overlap connective tissue disease (4). Three patients received the Janssen/Johnson & Johnson vaccine; all others received either the two-dose Moderna or Pfizer/BioNTech mRNA series.

At a median of 32 days after vaccination, all but two of the patients (92%) who withheld mycophenolate had detectable antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, compared with 65% of those who continued the drug (P = .01). This calculated to patients who withheld the drug as having nearly sixfold higher odds for a positive antibody response (odds ratio, 5.8; 95% CI, 1.3-25.5; P = .02). The association remained statistically significant in an logistic regression analysis that was adjusted for age, sex, race, vaccine type, and use of rituximab and glucocorticoids.

The withholding group also had significantly higher median anti-RBD immunoglobulin titers than did the group that continued therapy (125 vs. 7 U/L; P = .004).

Two patients who reported a flare of their underlying disease during the perivaccination period were treated with topical and oral glucocorticoids.

The patients who withdrew mycophenolate had taken it with twice daily dosing at a median total daily dose of 2,000 mg. They ended up withholding a median of 20 doses around the time of vaccination, with 54% withholding before, 38% both before and after, and 8% only after vaccination.

The researchers said that the conclusions that can be drawn from the study were limited by its small sample size, which “did not allow for evaluation of optimal duration of withholding therapy,” and also its “nonrandomized design, lack of data on cellular response, and limited information on dosing of other immunosuppressive agents.”

Three of the authors disclosed receiving consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, and Thermo Fisher Scientific. A fourth author has received consulting fees from Janssen, Boehringer Ingelheim, Mallinckrodt, EMD Serono, Allogene, and ArgenX.

[email protected]

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

In the wake of the Centers for Disease Control and Prevention’s recommendation for a third COVID-19 mRNA vaccine dose for immunocompromised people and the Food and Drug Administration’s authorization of the third dose, the National Institute of Allergy and Infectious Diseases has begun a phase 2 trial to assess the antibody response to a booster dose of the Pfizer-BioNTech, Moderna, or Janssen vaccine in people with autoimmune disease who did not respond to their original COVID-19 vaccine regimen, according to an announcement.

The investigators of the trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, also want to determine if pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine.

The trial will specifically look at the effects of mycophenolate mofetil (MMF) or mycophenolic acid (MPA), and methotrexate (MTX), or receipt of B cell–depletion therapy such as rituximab within the past 12 months on immune response to a booster dose in people with systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, or pemphigus. They have to have either no serologic response to their initial COVID-19 vaccine regimen or a suboptimal response, defined as a Roche Elecsys Anti-SARS-CoV-2 S (RBD) result greater than or equal to 50 U/mL.

The results of studies conducted in solid-organ transplant recipients who take immunosuppressants showed that an extra dose of vaccine could improve the immune response to the vaccine in many of the individuals, which suggests that the same approach might work in people with autoimmune disease who need treatment with immunosuppressive drugs. Improving the immune response of people with autoimmune disease to COVID-19 vaccines is important because higher rates of severe COVID-19 and death have been reported in this group of patients than in the general population, and it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.

The open-label trial, conducted by the NIAID-funded Autoimmunity Centers of Excellence, aims to enroll 600 people aged 18 years and older with those conditions at 15-20 sites in the United States.

Because medications commonly taken by people with these conditions have been associated with poorer immune responses to vaccines, the trial will randomize the following two cohorts to stop or continue taking their immunosuppressive medication(s) or stop them before and after the booster according to protocol:

• Cohort 1 includes people who are taking MMF or MPA, without additional B cell–depleting medications or MTX.
• Cohort 2 includes people who are taking MTX without additional B cell–depleting medications or MMF/MPA.

A third, nonrandomized cohort consists of people who have received B cell–depletion therapy within the past 12 months regardless of whether they are also taking MMF/MPA or MTX.

Besides the cohort-specific exclusions, other rheumatic disease medications, including biologics, are allowed in the groups.

The primary outcome of the trial is the proportion of participants who have a protective antibody response at week 4. Secondary outcomes will examine various antibody responses at intervals, changes in disease activity across autoimmune diseases, adverse events, and SARS-CoV-2 infections out to 48 weeks.

Study participants will be followed for a total of 13 months. Preliminary results are expected in November 2021, according to the National Institutes of Health.

The trial is being led by Judith James, MD, PhD; Meggan Mackay, MD, MS; Dinesh Khanna, MBBS, MSc; and Amit Bar-Or, MD.

[email protected]

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

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

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

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

With the approval by the Food and Drug Administration of the calcineurin inhibitor voclosporin (Lupkynis) in January and belimumab (Benlysta) a month before that, clinicians now have new options for treating lupus nephritis in combination with a background immunosuppressive agent, such as mycophenolate mofetil.

But which combination should clinicians choose?

Brad Rovin, MD, a nephrologist with the Ohio State University Wexner Medical Center, Columbus, who worked on the phase 3 voclosprin trial, pointed to that drug’s fast reduction in proteinuria in a session of the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting. That effect on proteinuria is likely due to its effect on podocytes, special epithelial cells that cover the outside of capillaries in the kidney, he said.

These crucial cells have an elaborate cytoskeleton that is stabilized by the protein synaptopodin, which can be subject to harm from calcineurin. But because voclosporin blocks calcineurin, synaptopodin is protected, which consequently protects podocytes and the kidney, Dr. Rovin said.

“There’s a lot of data in the nephrology literature that suggests as you lose podocytes, you actually can develop glomerular sclerosis and loss of renal function,” he said. “In fact, if you lose a critical number of podocytes, then no matter what you do, the kidney is likely to progress to end-stage kidney disease.

“The way I think about it now is, what else do these drugs add? And this idea of preserving the histology of the kidney is really important, and this can be done with voclosporin,” Dr. Rovin said.

Belimumab is also hailed as an effective tool, particularly for the prevention of flares. In the trial leading to its approval), just under 16% of patients experienced a renal-related event or death over 2 years, compared with 28% of the group that received placebo. Those receiving belimumab had a 50% greater chance of reaching the primary efficacy renal response, which was defined as a ratio of urinary protein to creatinine of 0.7 or less, an estimated glomerular filtration rate that was no worse than 20% below the pre-flare value or at least 60 mL/min per 1.73 m², and no use of rescue therapy for treatment failure.

The endpoints in the belimumab lupus nephritis trial were “quite rigorous,” Richard A. Furie, MD, said in the same session at the meeting. Patients with class V lupus nephritis were included in the trial, although disease of this severity is known to be particularly difficult to treat, he noted.

“There’s little question that our patients with lupus nephritis will benefit from such a therapeutic approach” with belimumab and mycophenolate, said Dr. Furie, professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, N.Y. “But regardless of which combination clinicians use, we are making advances, and that means better outcomes for our patients with lupus and lupus nephritis.”

Graciela Alarcon, MD, MPH, professor emeritus of medicine at the University of Alabama at Birmingham, who moderated the discussion, said there is no sure answer regarding the best choice for clinicians.

“As long as there’s no head-to-head comparison between the two new compounds, I don’t think that the question can be answered,” she said.

Indeed, the answer for many clinicians might be that for certain patients, dual therapy isn’t necessary, Dr. Furie said.

“The fundamental question, before we choose the second drug, is whether a second drug should be chosen,” he said. “There’s a lot of people in the community who are just sticking to the old-fashioned algorithm and that is just choosing one drug, like mycophenolate. ... Others might pick a second drug, but not until they see that mycophenolate is not doing an effective job.”

All agreed that the response rates are still not optimal for patients with lupus nephritis, even with these new combinations – they are still only in the 30%-40% range.

“We haven’t really boosted the response rate to where we want it to be, at least as measured by our current measurements and composite renal response,” Dr. Rovin said.

With voclosporin’s protective effects and belimumab’s flare prevention, the two could potentially be used together at some point, he suggested.

“I think these two drugs show us the possibility that we might use them together and get rid of the older drugs, and really minimize the older drugs and then use them on a longer-term basis to preserve kidney function, as well as keep the lupus in check,” he said.

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

New efforts – including the development of drugs that target mitochondrial pathways and others that target androgen receptors selectively – are underway for treating sarcopenia in rheumatic diseases, but so far the results have been mixed, an expert said at the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting, held recently as a virtual event.

Addressing the problem of reduced muscle mass – experienced by many patients with rheumatic diseases, owing in part to the processes of inflammation and to pain interfering with exercise – is bound to help with outcomes, inasmuch as lean mass and fat mass are linked with disability and early mortality, said Joshua Baker, MD, associate professor of medicine at the University of Pennsylvania, Philadelphia.

Elamipretide, which works by stabilizing mitochondrial pathways that are disrupted in people with sarcopenia, in particular those with mitochondrial disorders, might be the most promising of the therapies being developed. In a study published last year, patients with mitochondrial myopathy experienced significant improvement in gait speed, fatigue, and physical function after 4 weeks, Dr. Baker said.

It’s “an interesting and exciting approach that we need to see more studies about in the future,” he said.

Studies of selective androgen receptor modulators (SARMs), which are similar to anabolic steroids but only target certain androgen receptors so as to prevent side effects, have been a letdown, Dr. Baker said. The idea with SARMs is to enhance growth of certain tissue, such as muscle, without causing side effects in other tissues. Previous trials found that although this approach increased muscle mass, it didn’t produce improvements in measures of physical function.

A myostatin/activin type II receptor blocker, bimagrumab, was recently found to boost lean mass but without improvement in physical function or gait speed.

Still, the focus on improving sarcopenia is an encouraging development, Dr. Baker said.

“New therapies are in the pipeline, and let’s be optimistic and hope that in the future we’ll have lots of options for these patients,” he said.

For now, resistance training remains the best way to tackle the problem. However, the need to have access to trainers, equipment, and gyms, as well as the presence of comorbidities, can make exercise difficult, he said. In addition, routine nutritional supplements, such as with vitamin D, have not been found to improve outcomes, he noted.

The sheer number of people with sarcopenia should make the search for better inventions a priority, suggested Maria Lorena Brance, MD, PhD, professor of medicine at the National University of Rosario, Argentina.

“Prevalence of sarcopenia is very high in autoimmune disease, with representation between 20% and 30%, depending on the pathology,” she said. “So it’s very important to study the presence of sarcopenia.”

Identifying the problem – by first noticing symptoms and then confirming with tests of muscle strength, such as grip tests – would be a big step, the panelists said. Dr. Baker said that among patients with obesity, sarcopenia is more likely to be overlooked, because such patients might not be weak in an absolute sense but might be weak relative to their size.

Dr. Brance said that it’s important to differentiate the value of vitamin D for someone with normal levels in comparison with someone who has a deficiency. Although evidence does not support the use of vitamin D supplements across the board, supplements have been shown to be helpful for patients with low vitamin D levels, she said.

Xavier Ricardo, MD, PhD, professor at Federal University of Rio Grande, Brazil, suggested that sarcopenia may differ from what meets the eye. At his hospital, researchers are studying sarcopenia in patients with systemic sclerosis and have found that in about 20% to 25% of patients, it is present in levels similar to those that occur in patients with rheumatoid arthritis. Researchers are now examining tissue from biopsies to see whether there are differences between the two conditions in the processes of muscle wasting.

“So far, we’re a little bit surprised,” he said. “We expected to have more sarcopenia in these patients, because they do look more frail, more cachexic sometimes.”

Dr. Baker has received consulting fees from Bristol-Myers Squibb, Burns-White, and Gilead. Dr. Ricardo has received consulting fees, speaker fees, or both from AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, and UCB. Dr. Brance has disclosed no relevant financial relationships.

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

New efforts – including the development of drugs that target mitochondrial pathways and others that target androgen receptors selectively – are underway for treating sarcopenia in rheumatic diseases, but so far the results have been mixed, an expert said at the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting, held recently as a virtual event.

Addressing the problem of reduced muscle mass – experienced by many patients with rheumatic diseases, owing in part to the processes of inflammation and to pain interfering with exercise – is bound to help with outcomes, inasmuch as lean mass and fat mass are linked with disability and early mortality, said Joshua Baker, MD, associate professor of medicine at the University of Pennsylvania, Philadelphia.

Elamipretide, which works by stabilizing mitochondrial pathways that are disrupted in people with sarcopenia, in particular those with mitochondrial disorders, might be the most promising of the therapies being developed. In a study published last year, patients with mitochondrial myopathy experienced significant improvement in gait speed, fatigue, and physical function after 4 weeks, Dr. Baker said.

It’s “an interesting and exciting approach that we need to see more studies about in the future,” he said.

Studies of selective androgen receptor modulators (SARMs), which are similar to anabolic steroids but only target certain androgen receptors so as to prevent side effects, have been a letdown, Dr. Baker said. The idea with SARMs is to enhance growth of certain tissue, such as muscle, without causing side effects in other tissues. Previous trials found that although this approach increased muscle mass, it didn’t produce improvements in measures of physical function.

A myostatin/activin type II receptor blocker, bimagrumab, was recently found to boost lean mass but without improvement in physical function or gait speed.

Still, the focus on improving sarcopenia is an encouraging development, Dr. Baker said.

“New therapies are in the pipeline, and let’s be optimistic and hope that in the future we’ll have lots of options for these patients,” he said.

For now, resistance training remains the best way to tackle the problem. However, the need to have access to trainers, equipment, and gyms, as well as the presence of comorbidities, can make exercise difficult, he said. In addition, routine nutritional supplements, such as with vitamin D, have not been found to improve outcomes, he noted.

The sheer number of people with sarcopenia should make the search for better inventions a priority, suggested Maria Lorena Brance, MD, PhD, professor of medicine at the National University of Rosario, Argentina.

“Prevalence of sarcopenia is very high in autoimmune disease, with representation between 20% and 30%, depending on the pathology,” she said. “So it’s very important to study the presence of sarcopenia.”

Identifying the problem – by first noticing symptoms and then confirming with tests of muscle strength, such as grip tests – would be a big step, the panelists said. Dr. Baker said that among patients with obesity, sarcopenia is more likely to be overlooked, because such patients might not be weak in an absolute sense but might be weak relative to their size.

Dr. Brance said that it’s important to differentiate the value of vitamin D for someone with normal levels in comparison with someone who has a deficiency. Although evidence does not support the use of vitamin D supplements across the board, supplements have been shown to be helpful for patients with low vitamin D levels, she said.

Xavier Ricardo, MD, PhD, professor at Federal University of Rio Grande, Brazil, suggested that sarcopenia may differ from what meets the eye. At his hospital, researchers are studying sarcopenia in patients with systemic sclerosis and have found that in about 20% to 25% of patients, it is present in levels similar to those that occur in patients with rheumatoid arthritis. Researchers are now examining tissue from biopsies to see whether there are differences between the two conditions in the processes of muscle wasting.

“So far, we’re a little bit surprised,” he said. “We expected to have more sarcopenia in these patients, because they do look more frail, more cachexic sometimes.”

Dr. Baker has received consulting fees from Bristol-Myers Squibb, Burns-White, and Gilead. Dr. Ricardo has received consulting fees, speaker fees, or both from AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, and UCB. Dr. Brance has disclosed no relevant financial relationships.

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

New efforts – including the development of drugs that target mitochondrial pathways and others that target androgen receptors selectively – are underway for treating sarcopenia in rheumatic diseases, but so far the results have been mixed, an expert said at the Pan American League of Associations for Rheumatology (PANLAR) 2021 Annual Meeting, held recently as a virtual event.

Addressing the problem of reduced muscle mass – experienced by many patients with rheumatic diseases, owing in part to the processes of inflammation and to pain interfering with exercise – is bound to help with outcomes, inasmuch as lean mass and fat mass are linked with disability and early mortality, said Joshua Baker, MD, associate professor of medicine at the University of Pennsylvania, Philadelphia.

Elamipretide, which works by stabilizing mitochondrial pathways that are disrupted in people with sarcopenia, in particular those with mitochondrial disorders, might be the most promising of the therapies being developed. In a study published last year, patients with mitochondrial myopathy experienced significant improvement in gait speed, fatigue, and physical function after 4 weeks, Dr. Baker said.

It’s “an interesting and exciting approach that we need to see more studies about in the future,” he said.

Studies of selective androgen receptor modulators (SARMs), which are similar to anabolic steroids but only target certain androgen receptors so as to prevent side effects, have been a letdown, Dr. Baker said. The idea with SARMs is to enhance growth of certain tissue, such as muscle, without causing side effects in other tissues. Previous trials found that although this approach increased muscle mass, it didn’t produce improvements in measures of physical function.

A myostatin/activin type II receptor blocker, bimagrumab, was recently found to boost lean mass but without improvement in physical function or gait speed.

Still, the focus on improving sarcopenia is an encouraging development, Dr. Baker said.

“New therapies are in the pipeline, and let’s be optimistic and hope that in the future we’ll have lots of options for these patients,” he said.

For now, resistance training remains the best way to tackle the problem. However, the need to have access to trainers, equipment, and gyms, as well as the presence of comorbidities, can make exercise difficult, he said. In addition, routine nutritional supplements, such as with vitamin D, have not been found to improve outcomes, he noted.

The sheer number of people with sarcopenia should make the search for better inventions a priority, suggested Maria Lorena Brance, MD, PhD, professor of medicine at the National University of Rosario, Argentina.

“Prevalence of sarcopenia is very high in autoimmune disease, with representation between 20% and 30%, depending on the pathology,” she said. “So it’s very important to study the presence of sarcopenia.”

Identifying the problem – by first noticing symptoms and then confirming with tests of muscle strength, such as grip tests – would be a big step, the panelists said. Dr. Baker said that among patients with obesity, sarcopenia is more likely to be overlooked, because such patients might not be weak in an absolute sense but might be weak relative to their size.

Dr. Brance said that it’s important to differentiate the value of vitamin D for someone with normal levels in comparison with someone who has a deficiency. Although evidence does not support the use of vitamin D supplements across the board, supplements have been shown to be helpful for patients with low vitamin D levels, she said.

Xavier Ricardo, MD, PhD, professor at Federal University of Rio Grande, Brazil, suggested that sarcopenia may differ from what meets the eye. At his hospital, researchers are studying sarcopenia in patients with systemic sclerosis and have found that in about 20% to 25% of patients, it is present in levels similar to those that occur in patients with rheumatoid arthritis. Researchers are now examining tissue from biopsies to see whether there are differences between the two conditions in the processes of muscle wasting.

“So far, we’re a little bit surprised,” he said. “We expected to have more sarcopenia in these patients, because they do look more frail, more cachexic sometimes.”

Dr. Baker has received consulting fees from Bristol-Myers Squibb, Burns-White, and Gilead. Dr. Ricardo has received consulting fees, speaker fees, or both from AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, and UCB. Dr. Brance has disclosed no relevant financial relationships.

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

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.

A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.

“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.

Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.

“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
 

Not just for cancer anymore

CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.

There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.

For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.

The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.

One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.

Anti-CD20 failures

B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.

“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.

In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
 

Case details

As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.

Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.

The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.

Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.

“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.

The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.

The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.

Unanswered questions

Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.

In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.

The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.

Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.

A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.

“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.

Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.

“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
 

Not just for cancer anymore

CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.

There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.

For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.

The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.

One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.

Anti-CD20 failures

B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.

“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.

In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
 

Case details

As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.

Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.

The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.

Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.

“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.

The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.

The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.

Unanswered questions

Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.

In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.

The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.

Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.

A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.

“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.

Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.

“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
 

Not just for cancer anymore

CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.

There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.

For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.

The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.

One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.

Anti-CD20 failures

B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.

“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.

In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
 

Case details

As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.

Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.

The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.

Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.

“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.

The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.

The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.

Unanswered questions

Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.

In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.

The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.