Rheumatoid Arthritis

Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.

The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.

This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.

Lucidology/Thinkstock

It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.

“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”

While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.

“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.

Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.

“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”

Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.

CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
 

A version of this article appeared on Medscape.com.

Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.

The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.

This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.

Lucidology/Thinkstock

It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.

“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”

While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.

“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.

Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.

“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”

Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.

CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
 

A version of this article appeared on Medscape.com.

Congress provided $10 million to fund arthritis research in the recently passed federal fiscal year 2024 budget.

The new arthritis program is part of the Department of Defense’s (DOD’s) Congressionally Directed Medical Research Programs (CDMRP), which provides dedicated funding to study certain diseases and health conditions.

This is the first stand-alone research program for arthritis of the CDMRP, though the organization had previously funded arthritis-related research through their other programs, including chronic pain management, joint warfighter medical, peer-reviewed orthopedic, peer-reviewed medical, and tick-borne disease programs.

Lucidology/Thinkstock

It is not yet known what specific aspects of arthritis this funding will go toward. The standard process for new programs involves speaking with researchers, clinicians, and individuals with these targeted health conditions to better understand research gaps and narrow focus, Akua Roach, PhD, the program manager for this new CDMRP arthritis research program, told this news organization.

“We’re not going to be able to solve every question,” she said, though the allocated $10 million is “a great number to do a lot of great work.”

While the CDMRP is under the DOD, research funding can go to studying patient populations outside of military personnel or veterans, she added.

“I think that is perhaps a common misconception that if you are getting funding from the DOD, that you have to have a DOD population, and that is not true,” she said.

Another misconception is that CDMRP funding only goes to military treatment facilities. In fact, on average, 92% of CDMRP funding goes to academia, industry, and other nonmilitary recipients, noted CDMRP Director Colonel Sarah Goldman.

“Anyone around the world can apply for funding,” she told this news organization. “We want to fund the best research.”

Because the funding is provided under the defense bill, there will be discussions around the military relevance of research, she added, which not only includes service members but also their families.

CDMRP anticipates that funding opportunities through this new arthritis research program will be available by July or August 2024.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

The rheumatologist of the future will see patients who have been assessed and triaged with artificial intelligence utilizing data from remote kiosk-placed ultrasound scanners and physician-directed algorithms. Practices will be broadly fueled by AI, which will screen charts, produce notes, handle prior authorizations and insurance issues, aid in earlier diagnoses, find patients for clinical trials, and maybe even suggest the next best therapy for individual patients.

Such is the future envisioned by Alvin F. Wells, MD, PhD, and John J. Cush, MD, who discussed the current and forthcoming reach of AI — and their own uses of it — at the 2024 Rheumatology Winter Clinical Symposium.

“We’re not at the stage where ChatGPT and AI can tell us what the next best therapy is, but we’re getting there,” said Dr. Cush, a rheumatologist based in Dallas and executive director of RheumNow.com. For now, he said, “AI affords us a truly big-time increase in efficiency. It helps you deal with your time constraints in managing information overload and task overload.”

Bruce Jancin/MDedge News

At a time when “PubMed doubles every 73 days ... and it’s getting harder and harder to stay abreast,” for example, new applications such as Scite, SciSpace, and Consensus can help curate, focus, and analyze the literature to match one’s own clinical interests. Such review tools are “just now getting into play and are evolving,” Dr. Cush said, noting that many but not all of them are based on ChatGPT, OpenAI’s chatbot that had a over 100 million users by January 2023 — just over a month after its version 3.5 was released.

For Dr. Wells, a rheumatologist and Midwest Region director in the department of rheumatology for the Advocate Health Medical Group in Franklin, Wisconsin, clinician-developed algorithms are helping his group assess patients — often remotely — and triage them to be seen fairly immediately by a rheumatologist versus in 4-6 weeks or in several months. “You can use AI to guide your access,” he said.

A patient “with a family history of RA, sed rate above 50, and osteopenia on x-rays” would be seen within a week, for example, while “another patient who’s had a [positive] ANA with no other symptoms, and maybe a family history, might be seen in 4-6 weeks,” said Dr. Wells, sharing his belief that “there is not a shortage of rheumatologists, [but a] shortage of using rheumatologists efficiently.”

Dr. Wells

AI for Improving Workflow

Current and future advances will enrich the intersection of AI and virtual medicine and improve outcomes and the rheumatologist-patient interaction, Dr. Wells said, pointing to research presented at the American College of Rheumatology (ACR) 2023 annual meeting on the use of computer vision technology for remotely assessing disease activity in rheumatoid arthritis (RA).

In the proof-of-concept “MeFisto” study, 28 patients with RA used an app that enabled computer vision inference of hand motion data. Upon recording, an algorithm tracked the mean degree change of joint angle on flexion and the mean time to maximal flexion for each joint.

The researchers found a strong correlation between flexion of the distal interphalangeal (DIP) joint and the Disease Activity Score in 28 joints, the Swollen Hand Joint Count, and the Tender Hand Joint Count. DIP flexion was found to be a significant predictor of low disease activity/remission and high disease activity, the researchers reported in their abstract.

“This blows you away — that a single camera on [one’s] smartphone can look at the manipulation of a hand … and that AI can tell me, there’s a chance this might be an inflammatory arthritis,” said Dr. Wells, noting that researchers are also developing ways to detect joint swelling in RA by AI.

AI can also be used for remote ultrasound scanning in RA, as evidenced by use of the ARTHUR system in Europe, he said. Developed by the Danish company ROPCA, the ARTHUR technology (Rheumatoid Arthritis Ultrasound Robot) interacts directly with the patient who has new joint pain or established RA to capture ultrasound images in grayscale and color flow of 11 joints per hand. AI analyzes the images and creates a report for the specialist.

“They’re trying to get a foothold in the US,” Dr. Wells said, sharing his prediction that similar technology will someday be seen not only in pharmacies but also — in support of equitable access — in locations such as grocery stores. “Again,” he said, “nothing will replace us. I’m taking all [such] information and saying, who needs to be seen in 7 days and who can wait.”
 

AI for Writing, for Improving Practice and Patient Care

To manage his “task overload,” Dr. Cush uses ChatGPT for jobs such as first drafts of articles and making PowerPoint slides. It must be used cautiously for medical writing, however, as inaccuracies and false data/fabricated information — some of which has been coined AI “hallucinations” — are not uncommon.

“It’s very good at manuscript drafts, at generating bibliographies … it can do systematic reviews, it can do network meta-analyses, and it can find trends and patterns that can very helpful when it comes to writing. But you have to know how it’s a tool, and how it can hurt you,” he said.

Researchers recently reported asking ChatGPT to write an editorial about “how AI may replace the rheumatologist in editorial writing,” Dr. Cush noted. ChatGPT was “very politically correct,” he quipped, because it wrote that AI is “a tool to help the rheumatologist, but not replace him.”

Publishers want to preserve human intelligence — critical thinking and the ability to interpret, for instance — and most of the top medical journals (those most often cited) have issued guidance on the use of generative AI. “One said AI can’t be attributed as an author because being an author carries with it accountability of the work, and AI can’t take responsibility,” Dr. Cush said. Journals also “are saying you can use AI but you have to be totally transparent about it … [how it’s used] has to be very well spelled out.”

In practice, chatbots can be used for summarizing medical records, drafting post-visit summaries, collecting patient feedback, reminding about vaccinations, and performing administrative functions. “It’s really limitless as to what chatbots can do,” Dr. Cush said. “The question is, [what is] really going to help you?”

Much of the research submitted for presentation at major rheumatology meetings over the years has had questionable real-world utility and value, he said. But in the future this will likely change. “Take the PsA [psoriatic arthritis] patient who hasn’t responded to methotrexate or apremilast [Otezla]. There are [so many] choices, and there really isn’t a clear one. Shouldn’t data guide us on whether an IL-23 is better than a JAK, or maybe a JAK preferred over a TNF for some reason?” Dr. Cush said. “That’s what we’re hoping will happen down the line.”

More realistic AI-guided clinical scenarios for now include the following: AI screens the chart of a 68-year-old with RA on methotrexate and etanercept who is following up, and retrieves pieces of history — an elevated C-reactive protein 3 months ago, for instance, and diverticulosis 5 years ago. “AI tells you, based on this, he may have active disease, and here are three medications covered by his insurance,” Dr. Wells said.

Or, in the case of a 58-year-old patient with RA who has scheduled a virtual follow-up visit after having been on methotrexate and hydroxychloroquine for 12 weeks, AI detects a low platelet count in her previsit labs and also sees that she received an MMR booster 5 weeks ago at a local CVS Minute Clinic. AI retrieves for the rheumatologist a review article about thrombocytopenic purpura after MMR vaccination.
 

AI for Drug Development, Clinical Trials

Dr. Cush is following with keen interest the integration of AI into the process of drug development, from drug discovery and biomarker evaluation to clinical trial efficiency and patient recruitment, as well as marketing. “A lot hasn’t been ‘rolled out’ or shown to us, but there’s a lot going on … everyone is investing,” he said. “The number one challenge is regulatory: How will the [Food and Drug Administration] handle AI-generated data sets or AI-generated or monitored trials?”

The FDA is working to ensure quality and utility of data and is rapidly “approving AI algorithms for use in medicine and healthcare,” he said.

AI’s ability to identify patients in populations can not only facilitate earlier diagnoses but can accelerate patient recruitment for clinical trials, Dr. Cush emphasized. He pointed to research presented at the ACR 2021 annual meeting in which a machine-learning algorithm was used with electronic health records in the United Kingdom to estimate the probability of a patient’s being diagnosed with axial spondyloarthritis (axSpA).

AI identified 89 best clinical predictors (out of 820 analyzed). When applying these predictors to the population, AI was able to differentiate patients with axSpA from healthy controls with a sensitivity of 75%, a specificity of 96%, and a positive predictive value of 81%. Such an application of AI “is ideal … It would make clinical trials more streamlined and productive,” he said.

The extent to which AI will lead to cost savings — in the pharmacology arena, for instance, or for Well’s medical group — is unknown, Dr. Cush and Dr. Wells said. And, of course, there are concerns about potential bias and abuse of AI. “The worry,” Dr. Cush said, “is, who’s watching?”

Dr. Wells disclosed that he has research support and has served as a member of advisory boards and/or speaker bureaus for 17 different pharmaceutical or medical technology companies. Dr. Cush disclosed relationships with AbbVie, Amgen, Bristol-Myers Squibb, Novartis, Sanofi, and UCB.

Patients diagnosed with rheumatoid arthritis (RA) and co-occurring anxiety or depression are less likely to achieve low disease activity (LDA) and better symptom control after 3 months of treatment, according to new research presented at the at the annual meeting of the Canadian Rheumatology Association.

The findings emphasized the importance of taking a multidisciplinary approach to RA treatment, said presenter Susan Bartlett, PhD, a professor in the Divisions of Clinical Epidemiology, Rheumatology, and Respiratory Epidemiology at McGill University in Montreal, Quebec, Canada.

McGill University

“In the absence of directly addressing anxiety and depression, people are not going to improve to the same extent we hope that they will,” she told this news organization.
 

Symptom Clusters in RA

In her research, presented on February 29, Dr. Bartlett explored how certain symptom clusters in RA predicted prognosis.

Symptom clusters are related symptoms that occur together and can be associated with worse outcomes than one symptom alone. Symptom science has been a growing interest in precision medicine, particularly for cancer, Dr. Bartlett noted, and this same approach could help pinpoint RA subtypes, disease trajectories, and personalized treatment.

In the study, Dr. Bartlett and colleagues used data from the Canadian Early Arthritis Cohort (CATCH), a multisite prospective research study following individuals with new-onset RA. They identified patients starting methotrexate (MTX) therapy who also had clinical and patient-reported outcome measures available. Individuals included in the analysis may have also been taking additional disease-modifying antirheumatic drugs beyond MTX.

Across the 310 selected individuals, researchers identified four key symptoms: Pain, fatigue, anxiety, and depression. Pain and fatigue were defined as physical symptoms, while anxiety and depression were classified as emotional symptoms. Results showed that the patients could be sorted into four distinct symptom clusters: Minimal symptoms (12%), mild physical and emotional symptoms (11%), moderate to severe pain and fatigue (40%), and moderate to severe physical and emotional symptoms (37%).

Researchers then followed patients during the first 6 months of treatment to evaluate if patients’ symptoms improved.

Symptom improvement mostly occurred during the first 3 months of treatment and remained consistent at 6 months. Overall, patients with moderate to severe emotional symptoms had a worse prognosis and were less likely to achieve milder symptoms than those who had only pain and fatigue or mild emotional symptoms. While 64% of patients in the moderate to severe physical symptoms group achieved minimal symptoms after 3 months of treatment, only 13% of patients with moderate to severe physical and emotional systems reported minimal symptoms during this same time frame.

The study builds on previous work that “suggests that there are different factors that we can identify around the time of diagnosis that point to how well a person is likely to respond,” Dr. Bartlett added. “What our work is showing pretty clearly [is that] the presence of anxiety and depression is one of those important markers.”
 

Patients With Depression Report Worse Disease Activity

In a related study, researchers from the University of Ottawa explored how depression in RA affected subjective and objective disease measures.

The study included patients from the Ottawa Rheumatology Comprehensive Treatment and Assessment (ORCHESTRA) clinic at The Ottawa Hospital, Ottawa, Ontario, Canada, which sees patients with inflammatory arthritis who are starting biologic therapy or switching to another biologic. The clinic is designed to take a more comprehensive approach to managing inflammatory arthritis, including addressing comorbidities such as cardiac disease, depression, and cancer. Patients seen at the clinic can opt to be included in the ORCHESTRA cohort to be a part of ongoing research.

From this cohort, researchers identified 98 patients with RA. At enrollment, patients were screened for depression using patient health questionnaire scores and asked about duration of morning stiffness and tender joint counts. Swollen joint counts, ultrasound, and clinical scores were used to evaluate disease activity.

In the study group, 47 patients had no depression, 21 patients had mild depression, and 30 patients had moderate to severe depression. Researchers found that subjective disease measures, including visual analog pain scale, health assessment questionnaire, and disease activity score in 28 joints were all higher in patients with depression; however, depression did not appear to affect objective disease measures, such as the Global OMERACT-EULAR Synovitis Score or Doppler scores.

While there is a known link between inflammation and depression, these findings suggest that depression is “a concomitant comorbidity just like cardiovascular disease, just like fibromyalgia, just like some other comorbidity that also needs to be addressed in its own right to improve the outcomes,” noted Elliot Hepworth, MD, a rheumatologist and ORCHESTRA clinic lead at The Ottawa Hospital, in an interview.

Dr. Hepworth presented the findings on March 1.

Dr. Elliot Hepworth

The data also suggested that patients with depression had poorer outcomes. For the 79 patients who had 3-month follow-up visit data, 43.9% of patients with no or mild depression achieved LDA and remission compared with 21.7% of patients with moderate to severe depression, though this difference was not statistically significant (P = .064). There was a similar trend for the 39 patients with 6-month follow-up data: Only 20% of patients with moderate to severe depression had reached LDA and remission compared with 37.9% of patients with no or mild depression (P = .445). The researchers noted this could be an issue with a smaller sample size.

“Every time more patients get added we approach closer to significance,” Dr. Hepworth added.
 

Some Disagreement, Same Takeaway

Commenting on the Ottawa study, Dr. Bartlett was skeptical of the conclusion that depression may not directly influence disease activity. “There’s just too much good evidence these days that [depression] very much coexists with worse disease activity,” she said. “It is not in the person’s head.”

Dr. Hepworth added that patient-reported outcomes are important for clinicians to address during treatment.

“There’s the tender joints, there’s the pain, there’s the fatigue, there’s the patient global assessment, which are subjective,” he said, “but that does not mean that they are not important. Those are important to the patient: That is how they’re living their life, and that is how they’re experiencing their disease.”

This is why efforts to treat depression in patients with RA such as cognitive behavioral therapy are so important, he said, to which Dr. Bartlett agreed.

“A comprehensive approach is required, which includes addressing depression,” she said. Otherwise, data show “that people just never make it to remission.”

The studies looked at different patient populations but ultimately complement each other, added Sibel Aydin, MD, a professor of medicine in the Division of Rheumatology at the University of Ottawa, Ottawa, Ontario, Canada, and senior author of the Ottawa study.

Dr. Sibel Aydin

“Two different cohorts with different patient populations still reached the same result,” she said. “If you don’t address the emotional aspect, you are not going to achieve the good outcomes.”

“It’s remarkable when you have two independent researchers coming to the same conclusion without ever talking to each other,” added Dr. Hepworth. “That really shows that this is something that’s pervasive, and it’s not just within our patient population.”

CATCH is funded by unrestricted research grants from programs with Pfizer, AbbVie, Roche, Sandoz, Fresenius Kabi, Organon, Viatris, JAMP, and Celltrion. Dr. Bartlett is president of the PROMIS Health Organization. She is a member of speakers bureaus or has consulted for Pfizer, Sandoz, Merck, Janssen, and Organon. Dr. Hepworth and Dr. Aydin declared no conflicts of interest.

A version of this article appeared on Medscape.com .

Patients diagnosed with rheumatoid arthritis (RA) and co-occurring anxiety or depression are less likely to achieve low disease activity (LDA) and better symptom control after 3 months of treatment, according to new research presented at the at the annual meeting of the Canadian Rheumatology Association.

The findings emphasized the importance of taking a multidisciplinary approach to RA treatment, said presenter Susan Bartlett, PhD, a professor in the Divisions of Clinical Epidemiology, Rheumatology, and Respiratory Epidemiology at McGill University in Montreal, Quebec, Canada.

McGill University

“In the absence of directly addressing anxiety and depression, people are not going to improve to the same extent we hope that they will,” she told this news organization.
 

Symptom Clusters in RA

In her research, presented on February 29, Dr. Bartlett explored how certain symptom clusters in RA predicted prognosis.

Symptom clusters are related symptoms that occur together and can be associated with worse outcomes than one symptom alone. Symptom science has been a growing interest in precision medicine, particularly for cancer, Dr. Bartlett noted, and this same approach could help pinpoint RA subtypes, disease trajectories, and personalized treatment.

In the study, Dr. Bartlett and colleagues used data from the Canadian Early Arthritis Cohort (CATCH), a multisite prospective research study following individuals with new-onset RA. They identified patients starting methotrexate (MTX) therapy who also had clinical and patient-reported outcome measures available. Individuals included in the analysis may have also been taking additional disease-modifying antirheumatic drugs beyond MTX.

Across the 310 selected individuals, researchers identified four key symptoms: Pain, fatigue, anxiety, and depression. Pain and fatigue were defined as physical symptoms, while anxiety and depression were classified as emotional symptoms. Results showed that the patients could be sorted into four distinct symptom clusters: Minimal symptoms (12%), mild physical and emotional symptoms (11%), moderate to severe pain and fatigue (40%), and moderate to severe physical and emotional symptoms (37%).

Researchers then followed patients during the first 6 months of treatment to evaluate if patients’ symptoms improved.

Symptom improvement mostly occurred during the first 3 months of treatment and remained consistent at 6 months. Overall, patients with moderate to severe emotional symptoms had a worse prognosis and were less likely to achieve milder symptoms than those who had only pain and fatigue or mild emotional symptoms. While 64% of patients in the moderate to severe physical symptoms group achieved minimal symptoms after 3 months of treatment, only 13% of patients with moderate to severe physical and emotional systems reported minimal symptoms during this same time frame.

The study builds on previous work that “suggests that there are different factors that we can identify around the time of diagnosis that point to how well a person is likely to respond,” Dr. Bartlett added. “What our work is showing pretty clearly [is that] the presence of anxiety and depression is one of those important markers.”
 

Patients With Depression Report Worse Disease Activity

In a related study, researchers from the University of Ottawa explored how depression in RA affected subjective and objective disease measures.

The study included patients from the Ottawa Rheumatology Comprehensive Treatment and Assessment (ORCHESTRA) clinic at The Ottawa Hospital, Ottawa, Ontario, Canada, which sees patients with inflammatory arthritis who are starting biologic therapy or switching to another biologic. The clinic is designed to take a more comprehensive approach to managing inflammatory arthritis, including addressing comorbidities such as cardiac disease, depression, and cancer. Patients seen at the clinic can opt to be included in the ORCHESTRA cohort to be a part of ongoing research.

From this cohort, researchers identified 98 patients with RA. At enrollment, patients were screened for depression using patient health questionnaire scores and asked about duration of morning stiffness and tender joint counts. Swollen joint counts, ultrasound, and clinical scores were used to evaluate disease activity.

In the study group, 47 patients had no depression, 21 patients had mild depression, and 30 patients had moderate to severe depression. Researchers found that subjective disease measures, including visual analog pain scale, health assessment questionnaire, and disease activity score in 28 joints were all higher in patients with depression; however, depression did not appear to affect objective disease measures, such as the Global OMERACT-EULAR Synovitis Score or Doppler scores.

While there is a known link between inflammation and depression, these findings suggest that depression is “a concomitant comorbidity just like cardiovascular disease, just like fibromyalgia, just like some other comorbidity that also needs to be addressed in its own right to improve the outcomes,” noted Elliot Hepworth, MD, a rheumatologist and ORCHESTRA clinic lead at The Ottawa Hospital, in an interview.

Dr. Hepworth presented the findings on March 1.

Dr. Elliot Hepworth

The data also suggested that patients with depression had poorer outcomes. For the 79 patients who had 3-month follow-up visit data, 43.9% of patients with no or mild depression achieved LDA and remission compared with 21.7% of patients with moderate to severe depression, though this difference was not statistically significant (P = .064). There was a similar trend for the 39 patients with 6-month follow-up data: Only 20% of patients with moderate to severe depression had reached LDA and remission compared with 37.9% of patients with no or mild depression (P = .445). The researchers noted this could be an issue with a smaller sample size.

“Every time more patients get added we approach closer to significance,” Dr. Hepworth added.
 

Some Disagreement, Same Takeaway

Commenting on the Ottawa study, Dr. Bartlett was skeptical of the conclusion that depression may not directly influence disease activity. “There’s just too much good evidence these days that [depression] very much coexists with worse disease activity,” she said. “It is not in the person’s head.”

Dr. Hepworth added that patient-reported outcomes are important for clinicians to address during treatment.

“There’s the tender joints, there’s the pain, there’s the fatigue, there’s the patient global assessment, which are subjective,” he said, “but that does not mean that they are not important. Those are important to the patient: That is how they’re living their life, and that is how they’re experiencing their disease.”

This is why efforts to treat depression in patients with RA such as cognitive behavioral therapy are so important, he said, to which Dr. Bartlett agreed.

“A comprehensive approach is required, which includes addressing depression,” she said. Otherwise, data show “that people just never make it to remission.”

The studies looked at different patient populations but ultimately complement each other, added Sibel Aydin, MD, a professor of medicine in the Division of Rheumatology at the University of Ottawa, Ottawa, Ontario, Canada, and senior author of the Ottawa study.

Dr. Sibel Aydin

“Two different cohorts with different patient populations still reached the same result,” she said. “If you don’t address the emotional aspect, you are not going to achieve the good outcomes.”

“It’s remarkable when you have two independent researchers coming to the same conclusion without ever talking to each other,” added Dr. Hepworth. “That really shows that this is something that’s pervasive, and it’s not just within our patient population.”

CATCH is funded by unrestricted research grants from programs with Pfizer, AbbVie, Roche, Sandoz, Fresenius Kabi, Organon, Viatris, JAMP, and Celltrion. Dr. Bartlett is president of the PROMIS Health Organization. She is a member of speakers bureaus or has consulted for Pfizer, Sandoz, Merck, Janssen, and Organon. Dr. Hepworth and Dr. Aydin declared no conflicts of interest.

A version of this article appeared on Medscape.com .

Patients diagnosed with rheumatoid arthritis (RA) and co-occurring anxiety or depression are less likely to achieve low disease activity (LDA) and better symptom control after 3 months of treatment, according to new research presented at the at the annual meeting of the Canadian Rheumatology Association.

The findings emphasized the importance of taking a multidisciplinary approach to RA treatment, said presenter Susan Bartlett, PhD, a professor in the Divisions of Clinical Epidemiology, Rheumatology, and Respiratory Epidemiology at McGill University in Montreal, Quebec, Canada.

McGill University

“In the absence of directly addressing anxiety and depression, people are not going to improve to the same extent we hope that they will,” she told this news organization.
 

Symptom Clusters in RA

In her research, presented on February 29, Dr. Bartlett explored how certain symptom clusters in RA predicted prognosis.

Symptom clusters are related symptoms that occur together and can be associated with worse outcomes than one symptom alone. Symptom science has been a growing interest in precision medicine, particularly for cancer, Dr. Bartlett noted, and this same approach could help pinpoint RA subtypes, disease trajectories, and personalized treatment.

In the study, Dr. Bartlett and colleagues used data from the Canadian Early Arthritis Cohort (CATCH), a multisite prospective research study following individuals with new-onset RA. They identified patients starting methotrexate (MTX) therapy who also had clinical and patient-reported outcome measures available. Individuals included in the analysis may have also been taking additional disease-modifying antirheumatic drugs beyond MTX.

Across the 310 selected individuals, researchers identified four key symptoms: Pain, fatigue, anxiety, and depression. Pain and fatigue were defined as physical symptoms, while anxiety and depression were classified as emotional symptoms. Results showed that the patients could be sorted into four distinct symptom clusters: Minimal symptoms (12%), mild physical and emotional symptoms (11%), moderate to severe pain and fatigue (40%), and moderate to severe physical and emotional symptoms (37%).

Researchers then followed patients during the first 6 months of treatment to evaluate if patients’ symptoms improved.

Symptom improvement mostly occurred during the first 3 months of treatment and remained consistent at 6 months. Overall, patients with moderate to severe emotional symptoms had a worse prognosis and were less likely to achieve milder symptoms than those who had only pain and fatigue or mild emotional symptoms. While 64% of patients in the moderate to severe physical symptoms group achieved minimal symptoms after 3 months of treatment, only 13% of patients with moderate to severe physical and emotional systems reported minimal symptoms during this same time frame.

The study builds on previous work that “suggests that there are different factors that we can identify around the time of diagnosis that point to how well a person is likely to respond,” Dr. Bartlett added. “What our work is showing pretty clearly [is that] the presence of anxiety and depression is one of those important markers.”
 

Patients With Depression Report Worse Disease Activity

In a related study, researchers from the University of Ottawa explored how depression in RA affected subjective and objective disease measures.

The study included patients from the Ottawa Rheumatology Comprehensive Treatment and Assessment (ORCHESTRA) clinic at The Ottawa Hospital, Ottawa, Ontario, Canada, which sees patients with inflammatory arthritis who are starting biologic therapy or switching to another biologic. The clinic is designed to take a more comprehensive approach to managing inflammatory arthritis, including addressing comorbidities such as cardiac disease, depression, and cancer. Patients seen at the clinic can opt to be included in the ORCHESTRA cohort to be a part of ongoing research.

From this cohort, researchers identified 98 patients with RA. At enrollment, patients were screened for depression using patient health questionnaire scores and asked about duration of morning stiffness and tender joint counts. Swollen joint counts, ultrasound, and clinical scores were used to evaluate disease activity.

In the study group, 47 patients had no depression, 21 patients had mild depression, and 30 patients had moderate to severe depression. Researchers found that subjective disease measures, including visual analog pain scale, health assessment questionnaire, and disease activity score in 28 joints were all higher in patients with depression; however, depression did not appear to affect objective disease measures, such as the Global OMERACT-EULAR Synovitis Score or Doppler scores.

While there is a known link between inflammation and depression, these findings suggest that depression is “a concomitant comorbidity just like cardiovascular disease, just like fibromyalgia, just like some other comorbidity that also needs to be addressed in its own right to improve the outcomes,” noted Elliot Hepworth, MD, a rheumatologist and ORCHESTRA clinic lead at The Ottawa Hospital, in an interview.

Dr. Hepworth presented the findings on March 1.

Dr. Elliot Hepworth

The data also suggested that patients with depression had poorer outcomes. For the 79 patients who had 3-month follow-up visit data, 43.9% of patients with no or mild depression achieved LDA and remission compared with 21.7% of patients with moderate to severe depression, though this difference was not statistically significant (P = .064). There was a similar trend for the 39 patients with 6-month follow-up data: Only 20% of patients with moderate to severe depression had reached LDA and remission compared with 37.9% of patients with no or mild depression (P = .445). The researchers noted this could be an issue with a smaller sample size.

“Every time more patients get added we approach closer to significance,” Dr. Hepworth added.
 

Some Disagreement, Same Takeaway

Commenting on the Ottawa study, Dr. Bartlett was skeptical of the conclusion that depression may not directly influence disease activity. “There’s just too much good evidence these days that [depression] very much coexists with worse disease activity,” she said. “It is not in the person’s head.”

Dr. Hepworth added that patient-reported outcomes are important for clinicians to address during treatment.

“There’s the tender joints, there’s the pain, there’s the fatigue, there’s the patient global assessment, which are subjective,” he said, “but that does not mean that they are not important. Those are important to the patient: That is how they’re living their life, and that is how they’re experiencing their disease.”

This is why efforts to treat depression in patients with RA such as cognitive behavioral therapy are so important, he said, to which Dr. Bartlett agreed.

“A comprehensive approach is required, which includes addressing depression,” she said. Otherwise, data show “that people just never make it to remission.”

The studies looked at different patient populations but ultimately complement each other, added Sibel Aydin, MD, a professor of medicine in the Division of Rheumatology at the University of Ottawa, Ottawa, Ontario, Canada, and senior author of the Ottawa study.

Dr. Sibel Aydin

“Two different cohorts with different patient populations still reached the same result,” she said. “If you don’t address the emotional aspect, you are not going to achieve the good outcomes.”

“It’s remarkable when you have two independent researchers coming to the same conclusion without ever talking to each other,” added Dr. Hepworth. “That really shows that this is something that’s pervasive, and it’s not just within our patient population.”

CATCH is funded by unrestricted research grants from programs with Pfizer, AbbVie, Roche, Sandoz, Fresenius Kabi, Organon, Viatris, JAMP, and Celltrion. Dr. Bartlett is president of the PROMIS Health Organization. She is a member of speakers bureaus or has consulted for Pfizer, Sandoz, Merck, Janssen, and Organon. Dr. Hepworth and Dr. Aydin declared no conflicts of interest.

A version of this article appeared on Medscape.com .

The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.

This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release. 

Wikimedia Commons/FitzColinGerald/Creative Commons License

Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:

• Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
• Adults with giant cell arteritis
• Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
• Patients aged 2 years or older with active systemic juvenile idiopathic arthritis

“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.

The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.

Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector. 

The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.

Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.

“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.

This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release. 

Wikimedia Commons/FitzColinGerald/Creative Commons License

Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:

• Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
• Adults with giant cell arteritis
• Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
• Patients aged 2 years or older with active systemic juvenile idiopathic arthritis

“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.

The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.

Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector. 

The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.

Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.

“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the biosimilar tocilizumab-aazg (Tyenne), Fresenius Kabi, the drug’s manufacturer, announced on March 7.

This is the second tocilizumab biosimilar approved by the regulatory agency and the first to be approved in both intravenous (IV) and subcutaneous formulations that are available with the reference product, Actemra, the company said in a press release. 

Wikimedia Commons/FitzColinGerald/Creative Commons License

Tocilizumab-aazg is an interleukin-6 (IL-6) receptor antagonist indicated for:

• Adults with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs
• Adults with giant cell arteritis
• Patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis
• Patients aged 2 years or older with active systemic juvenile idiopathic arthritis

“Fresenius Kabi is leading the way as the first company to receive FDA approval for both IV and subcutaneous formulations of its tocilizumab biosimilar and is available in prefilled syringe, pen injector, and vial presentations,” Fabrice Romanet, senior vice president of innovation and development at Fresenius Kabi Biopharma, said in a statement.

The FDA approved the first tocilizumab biosimilar, manufactured by Biogen, in late September 2023. It is administered by IV infusion.

Tocilizumab-aazg’s approval was based on outcome and safety data from a dozen clinical studies. The drug can be administered via intravenous formulation (20 mg/mL) or subcutaneously via a single-dose 162-mg/0.9-mL prefilled syringe or single-dose prefilled autoinjector. 

The most common side effects for tocilizumab-aazg include upper respiratory tract infections, headache, hypertension, and injection site reactions. The most serious side effects include serious infections, perforation of the stomach or intestines, hepatotoxicity, and changes in certain lab results.

Tocilizumab-aazg has already launched in 10 countries, Fresenius Kabi shared in the press release, and plans to launch in additional countries in 2024 and 2025. It is not clear when tocilizumab-aazg will be made available in the United States.

“In accordance with its patent settlement agreement with Genentech, Fresenius Kabi has a license to market its tocilizumab products in the United States commencing on the license dates, which are confidential,” the company noted.
 

A version of this article appeared on Medscape.com.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.

The Food and Drug Administration’s approval of leflunomide in September 1998 as a treatment for rheumatoid arthritis was sandwiched between the debuts of infliximab (Remicade and biosimilars) and etanercept (Enbrel) in August and November of that year, the latter of which was so exciting that “within 2 months you couldn’t get [it],” recalled Eric M. Ruderman, MD. And “like every middle child, [leflunomide] was underloved, underappreciated, and largely dismissed.”

Yet should it have been? Is it worth another look today?

Courtesy Michael Pollard

At the 2024 Rheumatology Winter Clinical Symposium, Dr. Ruderman reflected on some of the clinical trial data published after leflunomide’s approval that “got lost in the shuffle” of the rightful embrace of biologics in United States practice, and urged reconsideration of the loading strategy still advised in the drug’s labeling.

“I’m not telling you that you should be using [leflunomide] in place of biologics, instead of biologics, or before biologics … but it should be in your toolkit,” said Dr. Ruderman, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago. The drug “still has a role in RA, including in combination with methotrexate, and a potential role in other rheumatic diseases.”

“In our PsA clinic,” he noted, “we’ve actually not infrequently added leflunomide to some of the other agents we’ve been using.”
 

Key Findings Over the Years in RA

Leflunomide showed efficacy similar to that of sulfasalazine in a randomized trial published in 1999 that used primary endpoints of tender/swollen joints and physician and patient global scores. Then, against methotrexate, it proved just as efficacious in achieving at least 20% improvement in American College of Rheumatology composite response criteria (ACR20) over 52 weeks, and in meeting endpoints similar to those of the sulfasalazine trial, in two trials, one published in 1999 and another in 2000.

“So here were two big trials [comparing it with methotrexate] that suggested the drug was just as good as what had become our standard of care by that point,” Dr. Ruderman said.

Each of these three trials used a loading dose of 100 mg leflunomide for 3 days, followed by 20 mg daily. Sulfasalazine was initiated at 2 g and escalated over 4 weeks. Methotrexate was initiated in one of the trials at a dose of 7.5 mg, then increased to 15 mg in almost two-thirds of patients; in the other methotrexate trial the initial dose was 15 mg escalated over 3 months.

Side effects of leflunomide — GI issues, rash, alopecia (reversible), and elevated liver function tests — were similar across the trials, and represented “about the same toxicities as methotrexate,” he said.

Researchers then tested leflunomide as an add-on to methotrexate in patients who had inadequate response, which “was a little bit daunting since we were still concerned about the toxicity of methotrexate at this point,” Dr. Ruderman said. “The idea that we’d take another drug with similar toxicities and add it on to the methotrexate was a little scary.”

But it worked. Patients on a mean background dose of 16.5 mg methotrexate were randomized to placebo or to a 2-day leflunomide loading dose followed by 10 mg/day that could be escalated at 8 weeks to 20 mg if needed. At 6 months, 19.5% and 46.2%, respectively, met ACR20 (P < .001), and “interestingly,” he said, “adverse events were pretty similar” between combination therapy and methotrexate monotherapy.

“This was very much like all the studies we’ve seen over the years with new biologics — they were all added to background methotrexate,” he said. “And the truth is, the [46%] response seen when adding leflunomide to background methotrexate wasn’t very different from the 50% [ACR20] response you tend to see when you add a biologic.”

However, despite the study’s conclusion that combination therapy provided significant benefit to patients with inadequate response to methotrexate alone, “the drug got lost, because everyone was prescribing the biologics,” Dr. Ruderman said.

He said he found only one study comparing leflunomide with a biologic. In a notably small but well-designed study from Sri Lanka published in 2017, 40 patients with an inadequate response to methotrexate were randomized to low-dose rituximab (500 mg x 2) or 20 mg/day leflunomide (no loading dose). At week 24, ACR20 was nearly identical (85% vs 84%), with a similar rate of adverse events.

The researchers pointed out “that there’s a potential cost benefit in developing countries where biologics aren’t as accessible,” he said, agreeing that “the big opportunity for a drug like leflunomide is outside the US, where you don’t have access to the drugs we take advantage of all the time.”

A meeting participant from Canada pointed out that rheumatologists there are “mandated to use it for PsA in combination with methotrexate before we can get a biologic, and for RA we can use it with Plaquenil [hydroxychloroquine] and methotrexate before we get a biologic, so we’re using it all the time.”

Asked about efficacy, the physician said the combination with methotrexate is “absolutely” efficacious. “It works really well” he said. “The problem is, you really have to watch the white cell count and liver function … and the half-life is long.”

Indeed, Dr. Ruderman said during his talk, the plasma half-life of teriflunomide, its active metabolite, is 15.5 days, which is challenging when adverse events occur. “And it’s a terrible drug in young women thinking about pregnancy because it’s teratogenic and stays around,” he said.

Leflunomide, which, notably, was “developed specifically for RA from the get-go” and not borrowed from another specialty, works by blocking de novo pyrimidine synthesis, Dr. Ruderman said. T-cell activation requires the upregulation of pyrimidine production (salvage pathways are insufficient); the “drug prevents that” by inhibiting an enzyme that catalyzes conversion of dihydroorotate to orotate, which, in turn, is converted to pyrimidine ribonucleotides, he explained.

Other potential mechanisms of action have been proposed — mainly, inhibition of tumor necrosis factor signaling and inhibition of kinase activity, including the JAK/STAT pathway — but “there’s not great data for any of them,” he said.
 

Loading vs Not Loading, and Its Role in PsA and Other Diseases

“We stopped loading years ago because at 100 mg for 3 days in a row, everyone has GI issues,” Dr. Ruderman said. “It may have made sense from a pharmacokinetic standpoint because [based on the long half-life] you could get to a higher drug level quicker, but not a practical standpoint, because patients would stop the drug — they couldn’t take it.” The first study to examine the necessity of loading leflunomide in a “prospective, careful way” was published in 2013. It randomized 120 patients to 100 mg or 20 mg for 3 days, followed by a 3-month open-label period of 20 mg, and found no clinical benefit with loading but more diarrhea and elevated liver enzymes.

“It tells us something about how we need to think about half-lives,” he said. “Maybe [loading is] not necessary because the biological effects are different than the drug levels.”

In the PsA space, in 2004, researchers reported a double-blind randomized trial in which 190 patients with active PsA and cutaneous psoriasis with at least 3% body surface area involvement were randomized to receive leflunomide (a loading dose followed by 20 mg/day) or placebo for 24 weeks. Almost 60% of leflunomide-treated patients, compared with 30% of placebo-treated patients, were classified as responders by the Psoriatic Arthritis Response criteria (P < .0001), “which is a soft endpoint” but was utilized at the time, Dr. Ruderman said. The researchers noted improvements in ACR20 and skin responses as well, and toxicity was similar to that reported in the RA studies.

However, approval was never sought, and the drug was infrequently prescribed, “because etanercept came out for this disease, and then adalimumab … and then the world changed,” he said.

More recently, a single-center, double-blind, randomized trial that included 78 Dutch patients with PsA tested leflunomide plus methotrexate vs methotrexate monotherapy and was published in The Lancet Rheumatology. After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than that of the monotherapy group (34%; P = .019). Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events were more common in the methotrexate plus leflunomide group.

In an interview after the meeting, Dr. Ruderman explained that in his practice, about 15 years ago, leflunomide was sometimes prescribed as an alternative to a biologic change for patients whose skin disease improved significantly with ustekinumab (Stelara) but who “suddenly had more joint symptoms that they didn’t have before.”

And “we’ve found ourselves a bit recently with the same sort of story, where patients are prescribed IL-23 inhibitors like Skyrizi [risankizumab] and Tremfya [guselkumab] and their skin does really well but now they’re having more joint symptoms than previously,” he said. “Our choices are to switch to a whole different biologic, or to think about adding something as an adjunct — and maybe leflunomide is a reasonable option.”

In the last 5 years, Dr. Ruderman noted, randomized trial data has been published on leflunomide in lupus nephritis induction, and in lupus nephritis maintenance, as well as in IgG4-related disease.

Dr. Ruderman disclosed consulting and/or drug safety monitoring board work for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, Novartis, NS Pharma, and UCB.

TOPLINE:

Researchers have identified six blood biomarkers tied to changes in arterial inflammation in patients with rheumatoid arthritis (RA).

METHODOLOGY:

• Researchers selected 24 candidate blood biomarkers previously associated with both RA and systemic inflammation.
• They measured biomarkers in 109 patients in the , which tested whether different treatments for RA reduced arterial inflammation.
• Along with biomarkers, they measured arterial inflammation via [18F] fluorodeoxyglucose (FDG)-PET/CT scans at baseline and 24 weeks.

TAKEAWAY:

• Baseline levels of the biomarkers serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-4, and osteoprotegerin were associated with significant changes in arterial inflammation on FDG-PET/CT scans.
• Adding these biomarkers to predictive models improved the adjusted R2 from 0.20 to 0.32 (likelihood ratio test, P = .0005).
• Researchers plan to validate these associations in a larger, external patient cohort.

IN PRACTICE:

This study is too preliminary to have practical applications.

SOURCE:

The study, led by Daniel Solomon, MD, of Brigham and Women’s Hospital, Boston, was published on February 28 in the Journal of the American Heart Association.

DISCLOSURES:

The research was funded by a National Institutes of Health grant as well as the Foundation for the National Institutes of Health Biomarkers Consortium. Several authors reported salary support or consulting fees from pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

Researchers have identified six blood biomarkers tied to changes in arterial inflammation in patients with rheumatoid arthritis (RA).

METHODOLOGY:

• Researchers selected 24 candidate blood biomarkers previously associated with both RA and systemic inflammation.
• They measured biomarkers in 109 patients in the , which tested whether different treatments for RA reduced arterial inflammation.
• Along with biomarkers, they measured arterial inflammation via [18F] fluorodeoxyglucose (FDG)-PET/CT scans at baseline and 24 weeks.

TAKEAWAY:

• Baseline levels of the biomarkers serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-4, and osteoprotegerin were associated with significant changes in arterial inflammation on FDG-PET/CT scans.
• Adding these biomarkers to predictive models improved the adjusted R2 from 0.20 to 0.32 (likelihood ratio test, P = .0005).
• Researchers plan to validate these associations in a larger, external patient cohort.

IN PRACTICE:

This study is too preliminary to have practical applications.

SOURCE:

The study, led by Daniel Solomon, MD, of Brigham and Women’s Hospital, Boston, was published on February 28 in the Journal of the American Heart Association.

DISCLOSURES:

The research was funded by a National Institutes of Health grant as well as the Foundation for the National Institutes of Health Biomarkers Consortium. Several authors reported salary support or consulting fees from pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

Researchers have identified six blood biomarkers tied to changes in arterial inflammation in patients with rheumatoid arthritis (RA).

METHODOLOGY:

• Researchers selected 24 candidate blood biomarkers previously associated with both RA and systemic inflammation.
• They measured biomarkers in 109 patients in the , which tested whether different treatments for RA reduced arterial inflammation.
• Along with biomarkers, they measured arterial inflammation via [18F] fluorodeoxyglucose (FDG)-PET/CT scans at baseline and 24 weeks.

TAKEAWAY:

• Baseline levels of the biomarkers serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-4, and osteoprotegerin were associated with significant changes in arterial inflammation on FDG-PET/CT scans.
• Adding these biomarkers to predictive models improved the adjusted R2 from 0.20 to 0.32 (likelihood ratio test, P = .0005).
• Researchers plan to validate these associations in a larger, external patient cohort.

IN PRACTICE:

This study is too preliminary to have practical applications.

SOURCE:

The study, led by Daniel Solomon, MD, of Brigham and Women’s Hospital, Boston, was published on February 28 in the Journal of the American Heart Association.

DISCLOSURES:

The research was funded by a National Institutes of Health grant as well as the Foundation for the National Institutes of Health Biomarkers Consortium. Several authors reported salary support or consulting fees from pharmaceutical companies.

A version of this article appeared on Medscape.com.

Patients with rheumatoid arthritis (RA) whose symptoms improved after they started taking nonbiologic disease-modifying antirheumatic drugs also demonstrated restored balance in their oral and gut flora, which could potentially serve as a marker of how they’ll respond to DMARDs, an observational study in the United Kingdom found.

Reporting in the journal Rheumatology, researchers led by Nathan Danckert, PhD, a genetic epidemiology researcher at King’s College London, and Maxim Freidin, PhD, of the Queen Mary University of London, London, England, evaluated stool and saliva samples of 144 people recently diagnosed with RA before and after they started DMARD therapy.

ChrisChrisW/Getty Images

“We identified a partial restoration of the microbiome to a more eubiotic state in RA patients at 6 weeks and 12 weeks of DMARD treatment in participants [who] responded well to DMARD therapy,” they wrote. “This was further supported by long-term (> 1 year) treated DMARD RA participants with similar community shifts.” Microbiomes, they said, are “a promising diagnostic tool” for directing DMARD therapy.
 

Study Goal Not Met

The goal of the study was to determine whether the microbiome of patients before they began treatment with DMARDs could predict their response to therapy. The patients were enrolled in the IMRABIOME study. Eligible patients had inflammatory arthritis symptoms for a year or less and met the clinical criteria for RA. Most patients were taking methotrexate (134 at baseline, 77 at 12 weeks), but study participants were also taking sulfasalazine (16 at baseline, 14 at 12 weeks) or hydroxychloroquine (58 at baseline, 45 at 12 weeks) either in combination or as a stand-alone treatment.

The study found a total of 26 different stool microbes that decreased in patients who had a minimal clinically important improvement (MCII) after starting DMARD therapy. At 6 weeks, the most significant declines were in Prevotella species. At 12 weeks, the greatest declines were in Streptococcus. 

The researchers also developed models that used gut and oral metagenomes to predict MCII in patients starting DMARD therapy. They used a previously published microbiome dataset as a validation cohort for the model, but they acknowledged their models “were not as strong” as three previously published models. “Our findings support the hypothesis of DMARD restoration of a eubiotic gut microbiome when patient and treatment align,” the authors wrote.

They noted they had anticipated finding baseline microbiome samples that would help predict treatment responses. While baseline evaluation didn’t differentiate between responders and nonresponders, they wrote that a longitudinal analysis demonstrated changing microbiota and a positive response to therapy, with declining levels of Prevotella and Streptococcus species most pronounced at 6 and 12 weeks, respectively.

“Microbiomes provide a promising diagnostic tool for guiding therapeutic decisions in the future,” the study authors wrote.
 

Commentary

In commenting on the study, Gregg J. Silverman, MD, professor of medicine and pathology at the New York University School of Medicine, New York City, said it “was carefully performed, technically it was actually quite impressive, and the scale of the study actually was quite suitable.”

NYU School of Medicine

However, the study fell short of achieving its primary goal of using the microbiome to predict treatment response, he said. “Basically, they could not find there was anything they could correlate with clinical response rates, although they did find that the presence or absence of certain bacteria at 6 weeks or 12 weeks into treatment correlated with a clinical response,” he said.

The multiplicity of DMARDs used by the study population was “one of the complicating factors” of the study, Dr. Silverman said. “It would’ve been a much more easily interpreted study if it used just a single agent like methotrexate,” he said. “I think that’s problematic, but I do think this contributes to getting us a little further down the road of understanding how the microbiome can influence the pathogenesis of rheumatoid arthritis response to treatment.”

One of the questions surrounding the microbiome changes is whether they occurred because of the effect of the therapy itself or because the disease activity subsides, Dr. Silverman said. “So, you’re not sure if it’s cause or effect. There’s evidence to suggest that either could be true.”

This study adds to a 2022 study that found a similar effect with methotrexate, Dr. Silverman said. “They considered a lot of variables, and they considered a lot of potential confounding effects,” he said. “So, their data were well-considered, and they will actually hold up over time and contribute to the next range of studies that will be performed, no doubt, in this area.”

It would be better if those future studies focused on just one DMARD drug and studied the recovered bacteria in animal models to gain a better understanding of how they correlate to pathogenesis, Dr. Silverman added.

The study received funding from Versus Arthritis. Dr. Danckert, Dr. Freidin, and coauthors, as well as Dr. Silverman, reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Patients with rheumatoid arthritis (RA) whose symptoms improved after they started taking nonbiologic disease-modifying antirheumatic drugs also demonstrated restored balance in their oral and gut flora, which could potentially serve as a marker of how they’ll respond to DMARDs, an observational study in the United Kingdom found.

Reporting in the journal Rheumatology, researchers led by Nathan Danckert, PhD, a genetic epidemiology researcher at King’s College London, and Maxim Freidin, PhD, of the Queen Mary University of London, London, England, evaluated stool and saliva samples of 144 people recently diagnosed with RA before and after they started DMARD therapy.

ChrisChrisW/Getty Images

“We identified a partial restoration of the microbiome to a more eubiotic state in RA patients at 6 weeks and 12 weeks of DMARD treatment in participants [who] responded well to DMARD therapy,” they wrote. “This was further supported by long-term (> 1 year) treated DMARD RA participants with similar community shifts.” Microbiomes, they said, are “a promising diagnostic tool” for directing DMARD therapy.
 

Study Goal Not Met

The goal of the study was to determine whether the microbiome of patients before they began treatment with DMARDs could predict their response to therapy. The patients were enrolled in the IMRABIOME study. Eligible patients had inflammatory arthritis symptoms for a year or less and met the clinical criteria for RA. Most patients were taking methotrexate (134 at baseline, 77 at 12 weeks), but study participants were also taking sulfasalazine (16 at baseline, 14 at 12 weeks) or hydroxychloroquine (58 at baseline, 45 at 12 weeks) either in combination or as a stand-alone treatment.

The study found a total of 26 different stool microbes that decreased in patients who had a minimal clinically important improvement (MCII) after starting DMARD therapy. At 6 weeks, the most significant declines were in Prevotella species. At 12 weeks, the greatest declines were in Streptococcus. 

The researchers also developed models that used gut and oral metagenomes to predict MCII in patients starting DMARD therapy. They used a previously published microbiome dataset as a validation cohort for the model, but they acknowledged their models “were not as strong” as three previously published models. “Our findings support the hypothesis of DMARD restoration of a eubiotic gut microbiome when patient and treatment align,” the authors wrote.

They noted they had anticipated finding baseline microbiome samples that would help predict treatment responses. While baseline evaluation didn’t differentiate between responders and nonresponders, they wrote that a longitudinal analysis demonstrated changing microbiota and a positive response to therapy, with declining levels of Prevotella and Streptococcus species most pronounced at 6 and 12 weeks, respectively.

“Microbiomes provide a promising diagnostic tool for guiding therapeutic decisions in the future,” the study authors wrote.
 

Commentary

In commenting on the study, Gregg J. Silverman, MD, professor of medicine and pathology at the New York University School of Medicine, New York City, said it “was carefully performed, technically it was actually quite impressive, and the scale of the study actually was quite suitable.”

NYU School of Medicine

However, the study fell short of achieving its primary goal of using the microbiome to predict treatment response, he said. “Basically, they could not find there was anything they could correlate with clinical response rates, although they did find that the presence or absence of certain bacteria at 6 weeks or 12 weeks into treatment correlated with a clinical response,” he said.

The multiplicity of DMARDs used by the study population was “one of the complicating factors” of the study, Dr. Silverman said. “It would’ve been a much more easily interpreted study if it used just a single agent like methotrexate,” he said. “I think that’s problematic, but I do think this contributes to getting us a little further down the road of understanding how the microbiome can influence the pathogenesis of rheumatoid arthritis response to treatment.”

One of the questions surrounding the microbiome changes is whether they occurred because of the effect of the therapy itself or because the disease activity subsides, Dr. Silverman said. “So, you’re not sure if it’s cause or effect. There’s evidence to suggest that either could be true.”

This study adds to a 2022 study that found a similar effect with methotrexate, Dr. Silverman said. “They considered a lot of variables, and they considered a lot of potential confounding effects,” he said. “So, their data were well-considered, and they will actually hold up over time and contribute to the next range of studies that will be performed, no doubt, in this area.”

It would be better if those future studies focused on just one DMARD drug and studied the recovered bacteria in animal models to gain a better understanding of how they correlate to pathogenesis, Dr. Silverman added.

The study received funding from Versus Arthritis. Dr. Danckert, Dr. Freidin, and coauthors, as well as Dr. Silverman, reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Patients with rheumatoid arthritis (RA) whose symptoms improved after they started taking nonbiologic disease-modifying antirheumatic drugs also demonstrated restored balance in their oral and gut flora, which could potentially serve as a marker of how they’ll respond to DMARDs, an observational study in the United Kingdom found.

Reporting in the journal Rheumatology, researchers led by Nathan Danckert, PhD, a genetic epidemiology researcher at King’s College London, and Maxim Freidin, PhD, of the Queen Mary University of London, London, England, evaluated stool and saliva samples of 144 people recently diagnosed with RA before and after they started DMARD therapy.

ChrisChrisW/Getty Images

“We identified a partial restoration of the microbiome to a more eubiotic state in RA patients at 6 weeks and 12 weeks of DMARD treatment in participants [who] responded well to DMARD therapy,” they wrote. “This was further supported by long-term (> 1 year) treated DMARD RA participants with similar community shifts.” Microbiomes, they said, are “a promising diagnostic tool” for directing DMARD therapy.
 

Study Goal Not Met

The goal of the study was to determine whether the microbiome of patients before they began treatment with DMARDs could predict their response to therapy. The patients were enrolled in the IMRABIOME study. Eligible patients had inflammatory arthritis symptoms for a year or less and met the clinical criteria for RA. Most patients were taking methotrexate (134 at baseline, 77 at 12 weeks), but study participants were also taking sulfasalazine (16 at baseline, 14 at 12 weeks) or hydroxychloroquine (58 at baseline, 45 at 12 weeks) either in combination or as a stand-alone treatment.

The study found a total of 26 different stool microbes that decreased in patients who had a minimal clinically important improvement (MCII) after starting DMARD therapy. At 6 weeks, the most significant declines were in Prevotella species. At 12 weeks, the greatest declines were in Streptococcus. 

The researchers also developed models that used gut and oral metagenomes to predict MCII in patients starting DMARD therapy. They used a previously published microbiome dataset as a validation cohort for the model, but they acknowledged their models “were not as strong” as three previously published models. “Our findings support the hypothesis of DMARD restoration of a eubiotic gut microbiome when patient and treatment align,” the authors wrote.

They noted they had anticipated finding baseline microbiome samples that would help predict treatment responses. While baseline evaluation didn’t differentiate between responders and nonresponders, they wrote that a longitudinal analysis demonstrated changing microbiota and a positive response to therapy, with declining levels of Prevotella and Streptococcus species most pronounced at 6 and 12 weeks, respectively.

“Microbiomes provide a promising diagnostic tool for guiding therapeutic decisions in the future,” the study authors wrote.
 

Commentary

In commenting on the study, Gregg J. Silverman, MD, professor of medicine and pathology at the New York University School of Medicine, New York City, said it “was carefully performed, technically it was actually quite impressive, and the scale of the study actually was quite suitable.”

NYU School of Medicine

However, the study fell short of achieving its primary goal of using the microbiome to predict treatment response, he said. “Basically, they could not find there was anything they could correlate with clinical response rates, although they did find that the presence or absence of certain bacteria at 6 weeks or 12 weeks into treatment correlated with a clinical response,” he said.

The multiplicity of DMARDs used by the study population was “one of the complicating factors” of the study, Dr. Silverman said. “It would’ve been a much more easily interpreted study if it used just a single agent like methotrexate,” he said. “I think that’s problematic, but I do think this contributes to getting us a little further down the road of understanding how the microbiome can influence the pathogenesis of rheumatoid arthritis response to treatment.”

One of the questions surrounding the microbiome changes is whether they occurred because of the effect of the therapy itself or because the disease activity subsides, Dr. Silverman said. “So, you’re not sure if it’s cause or effect. There’s evidence to suggest that either could be true.”

This study adds to a 2022 study that found a similar effect with methotrexate, Dr. Silverman said. “They considered a lot of variables, and they considered a lot of potential confounding effects,” he said. “So, their data were well-considered, and they will actually hold up over time and contribute to the next range of studies that will be performed, no doubt, in this area.”

It would be better if those future studies focused on just one DMARD drug and studied the recovered bacteria in animal models to gain a better understanding of how they correlate to pathogenesis, Dr. Silverman added.

The study received funding from Versus Arthritis. Dr. Danckert, Dr. Freidin, and coauthors, as well as Dr. Silverman, reported no relevant financial relationships.

A version of this article appeared on Medscape.com.