Rheumatology News

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.

The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.

There have been only a few randomized controlled trials (RCTs) conducted on what the committee is calling Lyme Infection-Associated Chronic Illness (Lyme IACI) for now, and no National Institutes of Health (NIH)-funded RCTs in the past 20 years or so. It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.

“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”

Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.

Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.

“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
 

Incidence and Potential Mechanisms

Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)

His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”

PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.

In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.

The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.

The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.

One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”

Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.

“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.

Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.

The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.

At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.

And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.

Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.

Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
 

Need for Patient-Centered Outcomes

Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.

Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.

Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.

Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.

Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.

“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”

A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.

The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
 

A version of this article appeared on Medscape.com.

TOPLINE:

More gastrointestinal and nervous symptom adverse events (AEs) are linked to apremilast than deucravacitinib, which is associated with more cutaneous AEs, according to a retrospective comparison using US Food and Drug Administration (FDA) data.

METHODOLOGY:

• To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
• The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
• AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.

TAKEAWAY:

• There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
• The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
• The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
• Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.

IN PRACTICE:

The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.

SOURCE:

Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.

LIMITATIONS:

The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.

DISCLOSURES:

The study received no funding, and the authors had no relevant financial disclosures.

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

TOPLINE:

More gastrointestinal and nervous symptom adverse events (AEs) are linked to apremilast than deucravacitinib, which is associated with more cutaneous AEs, according to a retrospective comparison using US Food and Drug Administration (FDA) data.

METHODOLOGY:

• To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
• The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
• AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.

TAKEAWAY:

• There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
• The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
• The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
• Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.

IN PRACTICE:

The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.

SOURCE:

Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.

LIMITATIONS:

The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.

DISCLOSURES:

The study received no funding, and the authors had no relevant financial disclosures.

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

TOPLINE:

More gastrointestinal and nervous symptom adverse events (AEs) are linked to apremilast than deucravacitinib, which is associated with more cutaneous AEs, according to a retrospective comparison using US Food and Drug Administration (FDA) data.

METHODOLOGY:

• To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
• The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
• AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.

TAKEAWAY:

• There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
• The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
• The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
• Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.

IN PRACTICE:

The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.

SOURCE:

Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.

LIMITATIONS:

The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.

DISCLOSURES:

The study received no funding, and the authors had no relevant financial disclosures.

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

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

TOPLINE:

Rates of major adverse cardiovascular events (MACE) do not differ significantly among individual biologics used for psoriasis or psoriatic arthritis (PsA), a database analysis finds. 

METHODOLOGY:

• Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
• The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
• Subset analyses compared MACE in patients with and without existing cardiovascular disease.

TAKEAWAY:

• Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
• There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.

IN PRACTICE:

Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.

SOURCE:

Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. 

LIMITATIONS:

The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.

DISCLOSURES:

Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.

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

Receipt of a newer recombinant version of a shingles vaccine is associated with a significant delay in dementia diagnosis in older adults, a new study suggests.

The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine. 

“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England. 

But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk. 

“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said. 

The study was published online on July 25 in Nature Medicine.
 

‘Natural Experiment’

Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection. 

The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017. 

Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch. 

They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020. 

Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected. 

As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%. 

Reduced Risk or Delayed Diagnosis?

Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.

“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained. 

But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported. 

“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested. 

But the researchers cautioned that this study could not prove causality. 

“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned. 

The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom. 

Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older. 

In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.  
 

Mechanism Uncertain

Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.

“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted. 

The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role. 

“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said. 
 

Stronger Effect in Women

Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men. 

In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women. 

In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine. 

As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect. 

“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented. 

Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study. 

He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine. 

“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented. 
 

Outside Experts Positive 

Outside experts, providing comment to the Science Media Centre, welcomed the new research. 

“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association. 

The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.

“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”

Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.

In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality. 

“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.

Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.

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

Receipt of a newer recombinant version of a shingles vaccine is associated with a significant delay in dementia diagnosis in older adults, a new study suggests.

The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine. 

“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England. 

But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk. 

“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said. 

The study was published online on July 25 in Nature Medicine.
 

‘Natural Experiment’

Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection. 

The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017. 

Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch. 

They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020. 

Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected. 

As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%. 

Reduced Risk or Delayed Diagnosis?

Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.

“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained. 

But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported. 

“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested. 

But the researchers cautioned that this study could not prove causality. 

“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned. 

The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom. 

Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older. 

In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.  
 

Mechanism Uncertain

Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.

“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted. 

The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role. 

“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said. 
 

Stronger Effect in Women

Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men. 

In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women. 

In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine. 

As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect. 

“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented. 

Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study. 

He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine. 

“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented. 
 

Outside Experts Positive 

Outside experts, providing comment to the Science Media Centre, welcomed the new research. 

“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association. 

The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.

“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”

Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.

In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality. 

“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.

Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.

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

Receipt of a newer recombinant version of a shingles vaccine is associated with a significant delay in dementia diagnosis in older adults, a new study suggests.

The study builds on previous observations of a reduction in dementia risk with the older live shingles vaccine and reports a delay in dementia diagnosis of 164 days with the newer recombinant version, compared with the live vaccine. 

“Given the prevalence of dementia, a delay of 164 days in diagnosis would not be a trivial effect at the public health level. It’s a big enough effect that if there is a causality it feels meaningful,” said senior author Paul Harrison, DM, FRCPsych, professor of psychiatry at the University of Oxford, Oxford, England. 

But Dr. Harrison stressed that the study had not proven that the shingles vaccine reduced dementia risk. 

“The design of the study allows us to do away with many of the confounding effects we usually see in observational studies, but this is still an observational study, and as such it cannot prove a definite causal effect,” he said. 

The study was published online on July 25 in Nature Medicine.
 

‘Natural Experiment’

Given the risk for deleterious consequences of shingles, vaccination is now recommended for older adults in many countries. The previously used live shingles vaccine (Zostavax) is being replaced in most countries with the new recombinant shingles vaccine (Shingrix), which is more effective at preventing shingles infection. 

The current study made use of a “natural experiment” in the United States, which switched over from use of the live vaccine to the recombinant vaccine in October 2017. 

Researchers used electronic heath records to compare the incidence of a dementia diagnosis in individuals who received the live shingles vaccine prior to October 2017 with those who received the recombinant version after the United States made the switch. 

They also used propensity score matching to further control for confounding factors, comparing 103,837 individuals who received a first dose of the live shingles vaccine between October 2014 and September 2017 with the same number of matched people who received the recombinant vaccine between November 2017 and October 2020. 

Results showed that within the 6 years after vaccination, the recombinant vaccine was associated with a delay in the diagnosis of dementia, compared with the live vaccine. Specifically, receiving the recombinant vaccine was associated with a 17% increase in diagnosis-free time, translating to 164 additional days lived without a diagnosis of dementia in those subsequently affected. 

As an additional control, the researchers also found significantly lower risks for dementia in individuals receiving the new recombinant shingles vaccine vs two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines, with increases in diagnosis-free time of 14%-27%. 

Reduced Risk or Delayed Diagnosis?

Speaking at a Science Media Centre press conference on the study, lead author Maxime Taquet, PhD, FRCPsych, clinical lecturer in psychiatry at the University of Oxford, noted that the total number of dementia cases were similar in the two shingles vaccine groups by the end of the 6-year follow-up period but there was a difference in the time at which they received a diagnosis of dementia.

“The study suggests that rather than actually reducing dementia risk, the recombinant vaccine delays the onset of dementia compared to the live vaccine in patients who go on to develop the condition,” he explained. 

But when comparing the recombinant vaccine with the influenza and tetanus/diphtheria/pertussis vaccines there was a clear reduction in dementia risk itself, Dr. Taquet reported. 

“It might well be that the live vaccine has a potential effect on the risk of dementia itself and therefore the recombinant vaccine only shows a delay in dementia compared to the live vaccine, but both of them might decrease the overall risk of dementia,” he suggested. 

But the researchers cautioned that this study could not prove causality. 

“While the two groups were very carefully matched in terms of factors that might influence the development of dementia, we still have to be cautious before assuming that the vaccine is indeed causally reducing the risk of onset of dementia,” Dr. Harrison warned. 

The researchers say the results would need to be confirmed in a randomized trial, which may have to be conducted in a slightly younger age group, as currently shingles vaccine is recommended for all older individuals in the United Kingdom. 

Vaccine recommendations vary from country to country, Dr. Harrison added. In the United States, the Centers for Disease Control and Prevention recommends the recombinant shingles vaccine for all adults aged 50 years or older. 

In the meantime, it would be interesting to see whether further observational studies in other countries find similar results as this US study, Dr. Harrison said.  
 

Mechanism Uncertain

Speculating on a possible mechanism behind the findings, Dr. Harrison suggested two plausible explanations.

“First, it is thought that the herpes virus could be one of many factors that could promote dementia, so a vaccine that stops reactivation of this virus might therefore be delaying that process,” he noted. 

The other possibility is that adjuvants included in the recombinant vaccine to stimulate the immune system might have played a role. 

“We don’t have any data on the mechanism, and thus study did not address that, so further studies are needed to look into this,” Dr. Harrison said. 
 

Stronger Effect in Women

Another intriguing finding is that the association with the recombinant vaccine and delayed dementia diagnosis seemed to be stronger in women vs men. 

In the original study of the live shingles vaccine, a protective effect against dementia was shown only in women. 

In the current study, the delay in dementia diagnosis was seen in both sexes but was stronger in women, showing a 22% increased time without dementia in women versus a 13% increased time in men with the recombinant versus the live vaccine. 

As expected, the recombinant vaccine was associated with a lower risk for shingles disease vs the live vaccine (2.5% versus 3.5%), but women did not have a better response than men did in this respect. 

“The better protection against shingles with the recombinant vaccine was similar in men and women, an observation that might be one reason to question the possible mechanism behind the dementia effect being better suppression of the herpes zoster virus by the recombinant vaccine,” Dr. Harrison commented. 

Though these findings are not likely to lead to any immediate changes in policy regarding the shingles vaccine, Dr. Harrison said it would be interesting to see whether uptake of the vaccine increased after this study. 

He estimated that, currently in the United Kingdom, about 60% of older adults choose to have the shingles vaccine. A 2020 study in the United States found that only about one-third of US adults over 60 had received the vaccine. 

“It will be interesting to see if that figure increases after these data are publicized, but I am not recommending that people have the vaccine specifically to lower their risk of dementia because of the caveats about the study that we have discussed,” he commented. 
 

Outside Experts Positive 

Outside experts, providing comment to the Science Media Centre, welcomed the new research. 

“ The study is very well-conducted and adds to previous data indicating that vaccination against shingles is associated with lower dementia risk. More research is needed in future to determine why this vaccine is associated with lower dementia risk,” said Tara Spires-Jones, FMedSci, president of the British Neuroscience Association. 

The high number of patients in the study and the adjustments for potential confounders are also strong points, noted Andrew Doig, PhD, professor of biochemistry, University of Manchester, Manchester, England.

“This is a significant result, comparable in effectiveness to the recent antibody drugs for Alzheimer’s disease,” Dr. Doig said. “Administering the recombinant shingles vaccine could well be a simple and cheap way to lower the risk of Alzheimer’s disease.”

Dr. Doig noted that a link between herpes zoster infection and the onset of dementia has been suspected for some time, and a trial of the antiviral drug valacyclovir against Alzheimer’s disease is currently underway.

In regard to the shingles vaccine, he said a placebo-controlled trial would be needed to prove causality. 

“We also need to see how many years the effect might last and whether we should vaccinate people at a younger age. We know that the path to Alzheimer’s can start decades before any symptoms are apparent, so the vaccine might be even more effective if given to people in their 40s or 50s,” he said.

Dr. Harrison and Dr. Taquet reported no disclosures. Dr. Doig is a founder, director, and consultant for PharmaKure, which works on Alzheimer’s drugs and diagnostics. Other commentators declared no disclosures.

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

“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed

What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.

Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.

Newtown grafitti / flickr / CC BY-2.0

Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.

Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.

In 2024, came our story’s deus ex machina: the AI scribe. A tool that can listen to a doctor visit, then from the ether, generate a note. A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.

Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.

AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.

Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.

Kaiser Permanente

Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.

The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”

Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.

“For sale. Sun hat. Never worn.”

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

“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed

What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.

Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.

Newtown grafitti / flickr / CC BY-2.0

Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.

Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.

In 2024, came our story’s deus ex machina: the AI scribe. A tool that can listen to a doctor visit, then from the ether, generate a note. A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.

Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.

AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.

Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.

Kaiser Permanente

Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.

The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”

Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.

“For sale. Sun hat. Never worn.”

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

“We really aren’t taking care of records — we’re taking care of people.” — Dr. Lawrence Weed

What is the purpose of a progress note? Anyone? Yes, you there. “Insurance billing?” Yes, that’s a good one. Anyone else? “To remember what you did?” Excellent. Another? Yes, that’s right, for others to follow along in your care. These are all good reasons for a progress note to exist. But they aren’t the whole story. Let’s start at the beginning.

Charts were once a collection of paper sheets with handwritten notes. Sometimes illegible, sometimes beautiful, always efficient. A progress note back then could be just 10 characters, AK, LN2, X,X,X,X,X (with X’s marking nitrogen sprays). Then came the healthcare K-Pg event: the conversion to EMRs. Those doctors who survived evolved into computer programmers, creating blocks of text from a few keystrokes. But like toddler-sized Legos, the blocks made it impossible to build a note that is nuanced or precise. Worse yet, many notes consisting of blocks from one note added awkwardly to a new note, creating grotesque structures unrecognizable as anything that should exist in nature. Words and numbers, but no information.

Newtown grafitti / flickr / CC BY-2.0

Thanks to the eternity of EMR, these creations live on, hideous and useless. They waste not only the server’s energy but also our time. Few things are more maddening than scrolling to reach the bottom of another physician’s note only to find there is nothing there.

Whose fault is this? Anyone? Yes, that’s right, insurers. As there are probably no payers in this audience, let’s blame them. I agree, the crushing burden of documentation-to-get-reimbursed has forced us to create “notes” that add no value to us but add up points for us to get paid for them. CMS, payers, prior authorizations, and now even patients, it seems we are documenting for lots of people except for us. There isn’t time to satisfy all and this significant burden for every encounter is a proximate cause for doctors despair. Until now.

In 2024, came our story’s deus ex machina: the AI scribe. A tool that can listen to a doctor visit, then from the ether, generate a note. A fully formed, comprehensive, sometimes pretty note that satisfies all audiences. Dr. Larry Weed must be dancing in heaven. It was Dr. Weed who led us from the nicotine-stained logs of the 1950s to the powerful problem-based notes we use today, an innovation that rivals the stethoscope in its impact.

Professor Weed also predicted that computers would be important to capture and make sense of patient data, helping us make accurate diagnoses and efficient plans. Again, he was right. He would surely be advocating to take advantage of AI scribes’ marvelous ability to capture salient data and present it in the form of a problem-oriented medical record.

AI scribes will be ubiquitous soon; I’m fast and even for me they save time. They also allow, for the first time in a decade, to turn from the glow of a screen to actually face the patient – we no longer have to scribe and care simultaneously. Hallelujah. And yet, lest I disappoint you without a twist, it seems with AI scribes, like EMRs we lose a little something too.

Like self-driving cars or ChatGPT-generated letters, they remove cognitive loads. They are lovely when you have to multitask or are trying to recall a visit from hours (days) ago. Using them, you’ll feel faster, lighter, freer, happier. But what’s missing is the thinking. At the end, you have an exquisite note, but you didn’t write it. It has the salient points, but none of the mental work to create it. AI scribes subvert the valuable work of synthesis. That was the critical part of Dr. Weed’s discovery: writing problem-oriented notes helped us think better.

Kaiser Permanente

Writing allows for the friction that helps us process what is going on with a patient. It allows for the discovery of diagnoses and prompts plans. When I was an intern, one of my attendings would hand write notes, succinctly showing what he had observed and was thinking. He’d sketch diagrams in the chart, for example, to help illustrate how we’d work though the toxic, metabolic, and infectious etiologies of acute liver failure. Sublime.

The act of writing also helps remind us there is a person attached to these words. Like a handwritten sympathy card, it is intimate, human. Even using our EMR, I’d still often type sentences that help tell the patient’s story. “Her sister just died. Utterly devastated. I’ll forward chart to Bob (her PCP) to check in on her.” Or: “Scratch golfer wants to know why he is getting so many SCCs now. ‘Like bankruptcy, gradually then suddenly,’ I explained. I think I broke through.”

Since we’ve concluded the purpose of a note is mostly to capture data, AI scribes are a godsend. They do so with remarkable quality and efficiency. We’ll just have to remember if the diagnosis is unclear, then it might help to write the note out yourself. And even when done by the AI machine, we might add human touches now and again lest there be no art left in what we do.

“For sale. Sun hat. Never worn.”

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

Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.

“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.

At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.

But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.

Sara Freeman/MDedge News

Societies Agree: Discontinue as Fast as Possible

GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.

Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.

Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.

Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.

The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.

EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.

For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.

EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
 

Low-Dose Approach Gains Ground

While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.

Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.

Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.

The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.

Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.

Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.

One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”

Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.

“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.

Debating the Toxicity Threshold

Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.

Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.

Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”

Bianca Nogrady/MDedge News

Tapering Options Across Diseases

Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.

In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.

For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.

However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”

All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.

A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.

For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.

Hospital for Special Surgery

What to Consider for AI Symptoms

Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.

Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.

Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.

Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
 

A version of this article appeared on Medscape.com.

Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.

“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.

At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.

But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.

Sara Freeman/MDedge News

Societies Agree: Discontinue as Fast as Possible

GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.

Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.

Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.

Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.

The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.

EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.

For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.

EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
 

Low-Dose Approach Gains Ground

While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.

Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.

Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.

The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.

Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.

Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.

One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”

Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.

“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.

Debating the Toxicity Threshold

Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.

Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.

Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”

Bianca Nogrady/MDedge News

Tapering Options Across Diseases

Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.

In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.

For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.

However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”

All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.

A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.

For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.

Hospital for Special Surgery

What to Consider for AI Symptoms

Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.

Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.

Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.

Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
 

A version of this article appeared on Medscape.com.

Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.

“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.

At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.

But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.

Sara Freeman/MDedge News

Societies Agree: Discontinue as Fast as Possible

GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.

Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.

Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.

Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.

The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.

EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.

For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.

EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
 

Low-Dose Approach Gains Ground

While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.

Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.

Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.

The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.

Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.

Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.

One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”

Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.

“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.

Debating the Toxicity Threshold

Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.

Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.

Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”

Bianca Nogrady/MDedge News

Tapering Options Across Diseases

Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.

In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.

For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.

However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”

All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.

A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.

For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.

Hospital for Special Surgery

What to Consider for AI Symptoms

Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.

Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.

Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.

Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
 

A version of this article appeared on Medscape.com.

New treatment strategies in clinical trials show promise in reducing the tapering time of glucocorticoids (GCs) or possibly even replacing the use of GCs. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.

“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.

GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.

HSD-1 Inhibitors Under Study

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.

Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.

GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.

During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.

A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.

“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.

An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.

Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.

In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
 

Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate

A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.

A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.

ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.

A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.

“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
 

C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs

Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.

A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.

Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.

Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.

Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.

Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.

In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.

Hospital for Special Surgery

A version of this article appeared on Medscape.com.

New treatment strategies in clinical trials show promise in reducing the tapering time of glucocorticoids (GCs) or possibly even replacing the use of GCs. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.

“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.

GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.

HSD-1 Inhibitors Under Study

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.

Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.

GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.

During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.

A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.

“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.

An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.

Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.

In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
 

Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate

A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.

A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.

ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.

A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.

“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
 

C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs

Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.

A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.

Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.

Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.

Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.

Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.

In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.

Hospital for Special Surgery

A version of this article appeared on Medscape.com.

New treatment strategies in clinical trials show promise in reducing the tapering time of glucocorticoids (GCs) or possibly even replacing the use of GCs. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.

“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.

GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.

HSD-1 Inhibitors Under Study

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.

Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.

GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.

During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.

A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.

“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.

An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.

Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.

In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
 

Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate

A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.

A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.

ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.

A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.

“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
 

C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs

Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.

A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.

Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.

Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.

Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.

Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.

In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.

Hospital for Special Surgery

A version of this article appeared on Medscape.com.