TBD Meeting (4660-24)

Preliminary findings from a small case-control study at the Mayo Clinic in Rochester, Minnesota, suggest an association between diet and the development of spondyloarthritis (SpA), researchers reported in a poster at the Rheumatology Winter Clinical Symposium.

The small study involving 106 cases of incident spondyloarthritis matched 5:1 to individuals without SpA on the basis of age, sex, year, and geography found that risk was significantly higher with consumption of nondiet soda (adjusted odds ratio [aOR], 1.76), and with use of certain supplements: folate (aOR, 2.56), B vitamins (1.98), and fish oil (1.83). Moderate alcohol use ranging from two servings per month up to five per week was associated with a significantly lower risk of SpA (aOR, 0.63).

“We have seen an association between diet and RA. There is also strong literature showing an association between the microbiome and spondyloarthritis. Putting these two together, we wanted to see if the same was true for spondyloarthritis,” Vanessa Kronzer, MD, a rheumatologist at Mayo Clinic and a coauthor of the poster, said in an email. “Our results … do suggest an association between diet and developing spondyloarthritis as we suspected, for example, with soda.”

The researchers enrolled patients through the Mayo Clinic Biobank, which aims to engage a population-based sample of primary care patients, and administered questionnaires that assessed dietary and supplement exposures. They identified incident SpA using two diagnosis codes for ankylosing spondylitis or PsA ≥ 30 days apart along with use of disease-modifying antirheumatic drugs. To identify inflammatory bowel disease–associated SpAs, they used two diagnosis codes ≥ 30 days apart and age < 45 years. Follow-up questionnaires were administered 5 years later, Dr. Kronzer said.

Controls were matched on age, sex, year and geography. Logistic regression models adjusted for age, sex, race and ethnicity, education, and smoking, the researchers reported in their poster.

Dr. Kronzer and coauthors reported finding no significant associations with high-fat food, red meat, fish, poultry, diet soda, coffee and tea, and high alcohol use. They reported finding “trends of reduced risk with fruits and vegetables but higher risk with milk/dairy” and said these trends “should be replicated in larger studies.”

The 106 patients with incident spondyloarthritis had a mean age of 51. Three-fourths were female.

The research was funded by the Rheumatology Research Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kronzer and coauthors did not report any disclosures.

Preliminary findings from a small case-control study at the Mayo Clinic in Rochester, Minnesota, suggest an association between diet and the development of spondyloarthritis (SpA), researchers reported in a poster at the Rheumatology Winter Clinical Symposium.

The small study involving 106 cases of incident spondyloarthritis matched 5:1 to individuals without SpA on the basis of age, sex, year, and geography found that risk was significantly higher with consumption of nondiet soda (adjusted odds ratio [aOR], 1.76), and with use of certain supplements: folate (aOR, 2.56), B vitamins (1.98), and fish oil (1.83). Moderate alcohol use ranging from two servings per month up to five per week was associated with a significantly lower risk of SpA (aOR, 0.63).

“We have seen an association between diet and RA. There is also strong literature showing an association between the microbiome and spondyloarthritis. Putting these two together, we wanted to see if the same was true for spondyloarthritis,” Vanessa Kronzer, MD, a rheumatologist at Mayo Clinic and a coauthor of the poster, said in an email. “Our results … do suggest an association between diet and developing spondyloarthritis as we suspected, for example, with soda.”

The researchers enrolled patients through the Mayo Clinic Biobank, which aims to engage a population-based sample of primary care patients, and administered questionnaires that assessed dietary and supplement exposures. They identified incident SpA using two diagnosis codes for ankylosing spondylitis or PsA ≥ 30 days apart along with use of disease-modifying antirheumatic drugs. To identify inflammatory bowel disease–associated SpAs, they used two diagnosis codes ≥ 30 days apart and age < 45 years. Follow-up questionnaires were administered 5 years later, Dr. Kronzer said.

Controls were matched on age, sex, year and geography. Logistic regression models adjusted for age, sex, race and ethnicity, education, and smoking, the researchers reported in their poster.

Dr. Kronzer and coauthors reported finding no significant associations with high-fat food, red meat, fish, poultry, diet soda, coffee and tea, and high alcohol use. They reported finding “trends of reduced risk with fruits and vegetables but higher risk with milk/dairy” and said these trends “should be replicated in larger studies.”

The 106 patients with incident spondyloarthritis had a mean age of 51. Three-fourths were female.

The research was funded by the Rheumatology Research Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kronzer and coauthors did not report any disclosures.

Preliminary findings from a small case-control study at the Mayo Clinic in Rochester, Minnesota, suggest an association between diet and the development of spondyloarthritis (SpA), researchers reported in a poster at the Rheumatology Winter Clinical Symposium.

The small study involving 106 cases of incident spondyloarthritis matched 5:1 to individuals without SpA on the basis of age, sex, year, and geography found that risk was significantly higher with consumption of nondiet soda (adjusted odds ratio [aOR], 1.76), and with use of certain supplements: folate (aOR, 2.56), B vitamins (1.98), and fish oil (1.83). Moderate alcohol use ranging from two servings per month up to five per week was associated with a significantly lower risk of SpA (aOR, 0.63).

“We have seen an association between diet and RA. There is also strong literature showing an association between the microbiome and spondyloarthritis. Putting these two together, we wanted to see if the same was true for spondyloarthritis,” Vanessa Kronzer, MD, a rheumatologist at Mayo Clinic and a coauthor of the poster, said in an email. “Our results … do suggest an association between diet and developing spondyloarthritis as we suspected, for example, with soda.”

The researchers enrolled patients through the Mayo Clinic Biobank, which aims to engage a population-based sample of primary care patients, and administered questionnaires that assessed dietary and supplement exposures. They identified incident SpA using two diagnosis codes for ankylosing spondylitis or PsA ≥ 30 days apart along with use of disease-modifying antirheumatic drugs. To identify inflammatory bowel disease–associated SpAs, they used two diagnosis codes ≥ 30 days apart and age < 45 years. Follow-up questionnaires were administered 5 years later, Dr. Kronzer said.

Controls were matched on age, sex, year and geography. Logistic regression models adjusted for age, sex, race and ethnicity, education, and smoking, the researchers reported in their poster.

Dr. Kronzer and coauthors reported finding no significant associations with high-fat food, red meat, fish, poultry, diet soda, coffee and tea, and high alcohol use. They reported finding “trends of reduced risk with fruits and vegetables but higher risk with milk/dairy” and said these trends “should be replicated in larger studies.”

The 106 patients with incident spondyloarthritis had a mean age of 51. Three-fourths were female.

The research was funded by the Rheumatology Research Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kronzer and coauthors did not report any disclosures.

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.”

Cush_John_J_TX_2_web.jpg

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.”

Wells_Alvin_WISC_web.png

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.”

Cush_John_J_TX_2_web.jpg

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.”

Wells_Alvin_WISC_web.png

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.”

Cush_John_J_TX_2_web.jpg

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.”

Wells_Alvin_WISC_web.png

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 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?

Ruderman_Eric_M_CHICAGO_web.jpg

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?

Ruderman_Eric_M_CHICAGO_web.jpg

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?

Ruderman_Eric_M_CHICAGO_web.jpg

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.

A Danish study showing that about half of patients with newly diagnosed inflammatory bowel disease (IBD) had findings consistent with spondyloarthritis (SpA) was highlighted as one of last year’s more actionable studies on SpA and axial SpA (axSpa) at the 2024 Rheumatology Winter Clinical Symposium (RWCS).

“There’s a lesson here,” said Eric M. Ruderman, MD, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago, Illinois. “We’ve spent a lot of time working with the dermatologists in the last 10 years to try to coordinate what we’re doing [for psoriatic disease]. It’s time to start working with the gastroenterologists more.”

Ruderman_Eric_M_IL_3_web.jpg

The findings offer “more evidence” for an increasingly documented overlap of IBD with SpA — whether axial or peripheral — and suggest there is underdiagnosis of SpA among patients with IBD. “It’s important,” he said at the meeting, “because if there are meaningful joint symptoms, this should be considered when making treatment choices [for IBD],” just as rheumatologists must be aware of the potential for IBD in choosing therapies.

Dr. Ruderman also urged rheumatologists making treatment decisions for axSpA to more carefully consider the role of central pain in driving residual symptoms in patients on biologic disease-modifying antirheumatic drugs (bDMARDs). He pointed to a 2023 study of patients with radiographic axSpA (r-axSpA) receiving bDMARDs that showed significant associations between high central pain and a greater odds of having higher disease activity, independent of elevated C-reactive protein (CRP) levels.

“I’ve come to the conclusion that there’s a huge amount of central pain in our patients — that it [affects] 20%-30% of our patients, no matter what rheumatologic disease they have,” he said, “and if you don’t acknowledge and consider that, you’ll keep churning through medications that aren’t going to work because you’re not addressing a fundamental issue.”

Among other key studies of 2023 highlighted by Dr. Ruderman was a large retrospective cohort study showing a similar incidence of ankylosing spondylitis (AS) in US military men and women screened for chronic back pain and the GO-BACK withdrawal and retreatment trial of golimumab suggesting that dosing can be extended.

Meanwhile, last year brought more bad news for interleukin (IL)-23 inhibition in axSpA, with the termination of a phase 2 study of tildrakizumab (Ilumya). Good news came with the US Food and Drug Administration approval in 2023 of an intravenous formulation of the IL-17 inhibitor secukinumab (Cosentyx), which will be helpful for some Medicare patients. And moving forward, the biologic pipeline is SpA is “almost all about new pathways in the IL-17 arena,” Dr. Ruderman said.

Making Good Drug Choices for the Gut and the Joints

In the study of SpA among patients with IBD, reported at the EULAR 2023 meeting in Milan, Italy, rheumatologists assessed 110 consecutive patients — 34% of whom were diagnosed with Crohn’s disease and 59% of whom had ulcerative colitis — from a Danish IBD inception cohort. The patients, about 40% of whom were male, had a mean age of 42.

At the time of IBD diagnosis, 49% had arthralgias/musculoskeletal symptoms, 52% fulfilled Assessment of SpondyloArthritis International Society (ASAS) classification criteria for peripheral SpA, and 49% had synovitis and/or enthesitis verified by ultrasound, Dr. Ruderman said.

Gastroenterologists like the integrin antagonist vedolizumab (Entyvio) for some patients with IBD because “it’s a very gut-specific drug and doesn’t have as much impact on the systemic immune system as other drugs, but because it’s gut specific, it does nothing for peripheral or axial joint symptoms,” Dr. Ruderman said in an interview after the meeting. “We’ve seen patients switched to this drug from Humira [or other biologics] and suddenly they have joint pains they never had before.”

The IL-12/23 inhibitor ustekinumab (Stelara) and the IL-23 inhibitor risankizumab (Skyrizi) are also sometimes selected for IBD, but “neither work well for patients with confirmed axSpA or inflammatory axial spine pain and arthritis,” he said. “Maybe these patients belong on a TNF [tumor necrosis factor] inhibitor or a JAK [Janus kinase] inhibitor, which will manage both the joints and the gut.”

“It’s not that we don’t talk to one another, but as we get more and more drugs in this space — both us and the gastroenterologists — it behooves us to communicate better to make sure we’re making the right choices for patients,” Dr. Ruderman said in the interview.

On the flip side, there’s a clear link between patients with axSpA who have or later develop IBD, as was further documented in 2023 by a multicenter Spanish study that evaluated patients with SpA (including both radiographic and nonradiographic axSpA) for the prevalence of undiagnosed IBD, Dr. Ruderman said at the RWCS.

The study, reported at the American College of Rheumatology (ACR) 2023 annual meeting, included only patients who were bDAMRD-naive and off of steroids for at least 30 days. The researchers used elevated fecal calprotectin levels (≥ 80 mcg/g) followed by colonoscopy — and an endoscopic capsule study or MRI if colonoscopy was normal — to confirm a diagnosis of IBD. Of 559 patients, 4.4% had such a confirmed diagnosis (95% with Crohn’s disease), and interestingly, only 30% of these patients had clinical IBD symptoms.

“These are people who had no suspicion,” Dr. Ruderman said at the meeting. “You could say that maybe not having symptoms is not a big deal, but over time, maybe there will be consequences.”

The IL-17 inhibitors ixekizumab (Taltz), secukinumab, and bimekizumab (Bimzelx) are generally felt to be contraindicated in patients who have confirmed IBD, Dr. Ruderman noted in the interview. “While we don’t want to necessarily avoid those drugs, we need to be aware of the potential [for IBD],” he said, “and we need to have a low threshold of suspicion if our patients develop any GI symptoms.”

Considering Noninflammatory Residual Pain

The 2023 central pain study that caught Dr. Ruderman’s attention — research reported at the EULAR 2023 meeting — looked at 70 patients with r-axSpA receiving bDMARD treatment (mostly TNF inhibitors) who were being followed in an extension of the German Spondyloarthritis Inception Cohort. Investigators used the Widespread Pain Index (WPI) to help quantify central pain/central sensitization and the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) to measure disease activity.

“Central pain was actually associated with having residual symptoms,” Dr. Ruderman said at the RWCS. Higher WPI scores were significantly associated with higher ASDAS-CRP scores, and a high WPI was also associated with higher odds of having high or very high disease activity (ASDAS > 2.1), independent of other factors including elevated CRP, the investigators reported in their abstract.

Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, commented that “we don’t have great [non-opioid] treatments for pain,” prompting Dr. Ruderman to emphasize the importance of “resisting the urge to [automatically] switch to another biologic” without trying to discern whether residual pain is inflammatory or noninflammatory in nature.

“I’m really comfortable with this,” Dr. Ruderman said, noting that he prescribes drugs like duloxetine or pregabalin for suspected central pain. “For the statin (for cardiovascular disease prevention), I’m more likely to turn back to the primary care physician and work with them, but here it’s part of what we’re treating — it becomes part of our tool kits.”

The central pain issue, Dr. Ruderman said after the meeting, is one of recognition and nomenclature. In the last few years, “there’s been a tendency to get away from secondary fibromyalgia as a label. There’s a lot of baggage with the diagnosis, unfortunately,” he said in the interview. “And it’s all connected. … It’s very likely that the [central] pain signaling is triggered by the inflammatory pain in the first place.”

A New Look at Sex-Specific Incidence of AS

The study on AS in a retrospective cohort of 729,000 working-age US military service members “flew under the radar,” but its finding of a similar incidence in men and women who underwent screening for chronic back pain is “fascinating,” Dr. Ruderman said. Compared with females, men were not significantly more likely to have a diagnosis of AS (adjusted odds ratio [OR], 0.79; 95% CI, 0.61-1.02; P = .072), the researchers reported.

“We’ve always assumed that AS is a male disease, and that, as we got into nonradiographic axSpA, we would see more women. This study calls that into question,” he said.

More Light on bDMARD Dosage Extension and Withdrawal

The GO-BACK study of the TNF inhibitor golimumab (Simponi) randomized 188 patients with inactive nonradiographic axSpA after 6 months of 50 mg golimumab monthly to treatment withdrawal/monthly placebo, continued monthly treatment, or treatment every 2 months. The take-home message, Dr. Ruderman said, is that “withdrawal, but not reduction in dose, led to a higher risk of flare.”

Also notable in this study published in 2023 is that “almost 100% of those who flared were recaptured with the reinitiation of monthly dosing,” he said. “So you don’t lose if you try to stop … [although] I don’t think that will ever be a successful strategy.” (The proportion of patients without a disease flare over 12 months was 34% in the withdrawal group, 68% in the extended dosing group, and 84% in the continued monthly treatment group.)

Dosing extensions have been shown to be potentially viable with other biologics, “but with this one, it looks like you can spread it out almost with impunity because it doesn’t look like there’s much difference” between continuing monthly and extending, Dr. Kavanaugh commented.

Another study from 2023 of the IL-17A inhibitor ixekizumab in axSpA similarly showed a high recapture rate for patients who withdrew from therapy and then flared. In this phase 3 extension study in which 155 patients with inactive or low-level disease were randomized at week 24 to continued ixekizumab or placebo, 53% of placebo patients flared by 2 years, compared with 13% in the ixekizumab arm. Of those who flared, 96% recaptured low disease activity with re-initiation of therapy.

“It’s the same story. You might get away with [stopping the therapy] because it’s not 100% who flared. But is it worth it?” Dr. Ruderman said.

IL-23 Inhibition in Axial Disease and the Pipeline

Is the chapter on IL-23 inhibitors closed for axSpA? Aside from a possible role for axial disease in psoriatic arthritis (PsA), it likely is, Dr. Ruderman said, pointing to the phase 2 randomized, double-blind, placebo-controlled study of tildrakizumab in patients with AS that was terminated at week 24 after the drug showed no difference in efficacy from placebo.

Dr. Kavanaugh agreed. “This adds to the data on risankizumab and ustekinumab in studies done properly in AS,” he said. “There’s no benefit.”

The “real issue” still to be determined, said Dr. Ruderman, “is what is the role of IL-23 inhibitors in patients with axial PsA?”

A post-hoc analysis of data from the SELECT PsA 1 and 2 trials, published in 2023, showed greater improvement in the overall Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score in patients with axial disease who received 15 mg upadacitinib (Rinvoq), compared with placebo.

“It suggests there’s improvement in the patients with axial PsA as defined [by a high BASDAI score], but they didn’t compare this with patients without axial disease … it’s muddy,” Dr. Ruderman said. Other research that’s underway should provide clarity, Dr. Kavanaugh said.

The pipeline for new treatments for SpA, including axSpA, is focused on new biologics targeting the IL-17 pathways, as well as a fair number of targeted synthetics, Dr. Ruderman said. “What will be interesting to me is what happens with the TYK2 inhibitors … because one of the postulated mechanisms is that the IL-23 signals through TYK-2,” he said. “So if that’s the mechanism, will they really help our patients with axial disease? We need the trials to find out.”

The intravenous formulation of secukinumab, approved in 2023 for AS, nr-axSpA, and PsA, is a “nice addition to our armamentarium, Dr. Ruderman noted in his 2023 review. “For years, a patient doing well on an IL-17 inhibitor for their axial disease or their psoriatic disease would hit Medicare age and suddenly couldn’t afford subcutaneous administration, and we had to switch them over to an IV-TNF inhibitor,” he said. “Now we have an IV IL-17 inhibitor.”

A Danish study showing that about half of patients with newly diagnosed inflammatory bowel disease (IBD) had findings consistent with spondyloarthritis (SpA) was highlighted as one of last year’s more actionable studies on SpA and axial SpA (axSpa) at the 2024 Rheumatology Winter Clinical Symposium (RWCS).

“There’s a lesson here,” said Eric M. Ruderman, MD, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago, Illinois. “We’ve spent a lot of time working with the dermatologists in the last 10 years to try to coordinate what we’re doing [for psoriatic disease]. It’s time to start working with the gastroenterologists more.”

Ruderman_Eric_M_IL_3_web.jpg

The findings offer “more evidence” for an increasingly documented overlap of IBD with SpA — whether axial or peripheral — and suggest there is underdiagnosis of SpA among patients with IBD. “It’s important,” he said at the meeting, “because if there are meaningful joint symptoms, this should be considered when making treatment choices [for IBD],” just as rheumatologists must be aware of the potential for IBD in choosing therapies.

Dr. Ruderman also urged rheumatologists making treatment decisions for axSpA to more carefully consider the role of central pain in driving residual symptoms in patients on biologic disease-modifying antirheumatic drugs (bDMARDs). He pointed to a 2023 study of patients with radiographic axSpA (r-axSpA) receiving bDMARDs that showed significant associations between high central pain and a greater odds of having higher disease activity, independent of elevated C-reactive protein (CRP) levels.

“I’ve come to the conclusion that there’s a huge amount of central pain in our patients — that it [affects] 20%-30% of our patients, no matter what rheumatologic disease they have,” he said, “and if you don’t acknowledge and consider that, you’ll keep churning through medications that aren’t going to work because you’re not addressing a fundamental issue.”

Among other key studies of 2023 highlighted by Dr. Ruderman was a large retrospective cohort study showing a similar incidence of ankylosing spondylitis (AS) in US military men and women screened for chronic back pain and the GO-BACK withdrawal and retreatment trial of golimumab suggesting that dosing can be extended.

Meanwhile, last year brought more bad news for interleukin (IL)-23 inhibition in axSpA, with the termination of a phase 2 study of tildrakizumab (Ilumya). Good news came with the US Food and Drug Administration approval in 2023 of an intravenous formulation of the IL-17 inhibitor secukinumab (Cosentyx), which will be helpful for some Medicare patients. And moving forward, the biologic pipeline is SpA is “almost all about new pathways in the IL-17 arena,” Dr. Ruderman said.

Making Good Drug Choices for the Gut and the Joints

In the study of SpA among patients with IBD, reported at the EULAR 2023 meeting in Milan, Italy, rheumatologists assessed 110 consecutive patients — 34% of whom were diagnosed with Crohn’s disease and 59% of whom had ulcerative colitis — from a Danish IBD inception cohort. The patients, about 40% of whom were male, had a mean age of 42.

At the time of IBD diagnosis, 49% had arthralgias/musculoskeletal symptoms, 52% fulfilled Assessment of SpondyloArthritis International Society (ASAS) classification criteria for peripheral SpA, and 49% had synovitis and/or enthesitis verified by ultrasound, Dr. Ruderman said.

Gastroenterologists like the integrin antagonist vedolizumab (Entyvio) for some patients with IBD because “it’s a very gut-specific drug and doesn’t have as much impact on the systemic immune system as other drugs, but because it’s gut specific, it does nothing for peripheral or axial joint symptoms,” Dr. Ruderman said in an interview after the meeting. “We’ve seen patients switched to this drug from Humira [or other biologics] and suddenly they have joint pains they never had before.”

The IL-12/23 inhibitor ustekinumab (Stelara) and the IL-23 inhibitor risankizumab (Skyrizi) are also sometimes selected for IBD, but “neither work well for patients with confirmed axSpA or inflammatory axial spine pain and arthritis,” he said. “Maybe these patients belong on a TNF [tumor necrosis factor] inhibitor or a JAK [Janus kinase] inhibitor, which will manage both the joints and the gut.”

“It’s not that we don’t talk to one another, but as we get more and more drugs in this space — both us and the gastroenterologists — it behooves us to communicate better to make sure we’re making the right choices for patients,” Dr. Ruderman said in the interview.

On the flip side, there’s a clear link between patients with axSpA who have or later develop IBD, as was further documented in 2023 by a multicenter Spanish study that evaluated patients with SpA (including both radiographic and nonradiographic axSpA) for the prevalence of undiagnosed IBD, Dr. Ruderman said at the RWCS.

The study, reported at the American College of Rheumatology (ACR) 2023 annual meeting, included only patients who were bDAMRD-naive and off of steroids for at least 30 days. The researchers used elevated fecal calprotectin levels (≥ 80 mcg/g) followed by colonoscopy — and an endoscopic capsule study or MRI if colonoscopy was normal — to confirm a diagnosis of IBD. Of 559 patients, 4.4% had such a confirmed diagnosis (95% with Crohn’s disease), and interestingly, only 30% of these patients had clinical IBD symptoms.

“These are people who had no suspicion,” Dr. Ruderman said at the meeting. “You could say that maybe not having symptoms is not a big deal, but over time, maybe there will be consequences.”

The IL-17 inhibitors ixekizumab (Taltz), secukinumab, and bimekizumab (Bimzelx) are generally felt to be contraindicated in patients who have confirmed IBD, Dr. Ruderman noted in the interview. “While we don’t want to necessarily avoid those drugs, we need to be aware of the potential [for IBD],” he said, “and we need to have a low threshold of suspicion if our patients develop any GI symptoms.”

Considering Noninflammatory Residual Pain

The 2023 central pain study that caught Dr. Ruderman’s attention — research reported at the EULAR 2023 meeting — looked at 70 patients with r-axSpA receiving bDMARD treatment (mostly TNF inhibitors) who were being followed in an extension of the German Spondyloarthritis Inception Cohort. Investigators used the Widespread Pain Index (WPI) to help quantify central pain/central sensitization and the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) to measure disease activity.

“Central pain was actually associated with having residual symptoms,” Dr. Ruderman said at the RWCS. Higher WPI scores were significantly associated with higher ASDAS-CRP scores, and a high WPI was also associated with higher odds of having high or very high disease activity (ASDAS > 2.1), independent of other factors including elevated CRP, the investigators reported in their abstract.

Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, commented that “we don’t have great [non-opioid] treatments for pain,” prompting Dr. Ruderman to emphasize the importance of “resisting the urge to [automatically] switch to another biologic” without trying to discern whether residual pain is inflammatory or noninflammatory in nature.

“I’m really comfortable with this,” Dr. Ruderman said, noting that he prescribes drugs like duloxetine or pregabalin for suspected central pain. “For the statin (for cardiovascular disease prevention), I’m more likely to turn back to the primary care physician and work with them, but here it’s part of what we’re treating — it becomes part of our tool kits.”

The central pain issue, Dr. Ruderman said after the meeting, is one of recognition and nomenclature. In the last few years, “there’s been a tendency to get away from secondary fibromyalgia as a label. There’s a lot of baggage with the diagnosis, unfortunately,” he said in the interview. “And it’s all connected. … It’s very likely that the [central] pain signaling is triggered by the inflammatory pain in the first place.”

A New Look at Sex-Specific Incidence of AS

The study on AS in a retrospective cohort of 729,000 working-age US military service members “flew under the radar,” but its finding of a similar incidence in men and women who underwent screening for chronic back pain is “fascinating,” Dr. Ruderman said. Compared with females, men were not significantly more likely to have a diagnosis of AS (adjusted odds ratio [OR], 0.79; 95% CI, 0.61-1.02; P = .072), the researchers reported.

“We’ve always assumed that AS is a male disease, and that, as we got into nonradiographic axSpA, we would see more women. This study calls that into question,” he said.

More Light on bDMARD Dosage Extension and Withdrawal

The GO-BACK study of the TNF inhibitor golimumab (Simponi) randomized 188 patients with inactive nonradiographic axSpA after 6 months of 50 mg golimumab monthly to treatment withdrawal/monthly placebo, continued monthly treatment, or treatment every 2 months. The take-home message, Dr. Ruderman said, is that “withdrawal, but not reduction in dose, led to a higher risk of flare.”

Also notable in this study published in 2023 is that “almost 100% of those who flared were recaptured with the reinitiation of monthly dosing,” he said. “So you don’t lose if you try to stop … [although] I don’t think that will ever be a successful strategy.” (The proportion of patients without a disease flare over 12 months was 34% in the withdrawal group, 68% in the extended dosing group, and 84% in the continued monthly treatment group.)

Dosing extensions have been shown to be potentially viable with other biologics, “but with this one, it looks like you can spread it out almost with impunity because it doesn’t look like there’s much difference” between continuing monthly and extending, Dr. Kavanaugh commented.

Another study from 2023 of the IL-17A inhibitor ixekizumab in axSpA similarly showed a high recapture rate for patients who withdrew from therapy and then flared. In this phase 3 extension study in which 155 patients with inactive or low-level disease were randomized at week 24 to continued ixekizumab or placebo, 53% of placebo patients flared by 2 years, compared with 13% in the ixekizumab arm. Of those who flared, 96% recaptured low disease activity with re-initiation of therapy.

“It’s the same story. You might get away with [stopping the therapy] because it’s not 100% who flared. But is it worth it?” Dr. Ruderman said.

IL-23 Inhibition in Axial Disease and the Pipeline

Is the chapter on IL-23 inhibitors closed for axSpA? Aside from a possible role for axial disease in psoriatic arthritis (PsA), it likely is, Dr. Ruderman said, pointing to the phase 2 randomized, double-blind, placebo-controlled study of tildrakizumab in patients with AS that was terminated at week 24 after the drug showed no difference in efficacy from placebo.

Dr. Kavanaugh agreed. “This adds to the data on risankizumab and ustekinumab in studies done properly in AS,” he said. “There’s no benefit.”

The “real issue” still to be determined, said Dr. Ruderman, “is what is the role of IL-23 inhibitors in patients with axial PsA?”

A post-hoc analysis of data from the SELECT PsA 1 and 2 trials, published in 2023, showed greater improvement in the overall Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score in patients with axial disease who received 15 mg upadacitinib (Rinvoq), compared with placebo.

“It suggests there’s improvement in the patients with axial PsA as defined [by a high BASDAI score], but they didn’t compare this with patients without axial disease … it’s muddy,” Dr. Ruderman said. Other research that’s underway should provide clarity, Dr. Kavanaugh said.

The pipeline for new treatments for SpA, including axSpA, is focused on new biologics targeting the IL-17 pathways, as well as a fair number of targeted synthetics, Dr. Ruderman said. “What will be interesting to me is what happens with the TYK2 inhibitors … because one of the postulated mechanisms is that the IL-23 signals through TYK-2,” he said. “So if that’s the mechanism, will they really help our patients with axial disease? We need the trials to find out.”

The intravenous formulation of secukinumab, approved in 2023 for AS, nr-axSpA, and PsA, is a “nice addition to our armamentarium, Dr. Ruderman noted in his 2023 review. “For years, a patient doing well on an IL-17 inhibitor for their axial disease or their psoriatic disease would hit Medicare age and suddenly couldn’t afford subcutaneous administration, and we had to switch them over to an IV-TNF inhibitor,” he said. “Now we have an IV IL-17 inhibitor.”

A Danish study showing that about half of patients with newly diagnosed inflammatory bowel disease (IBD) had findings consistent with spondyloarthritis (SpA) was highlighted as one of last year’s more actionable studies on SpA and axial SpA (axSpa) at the 2024 Rheumatology Winter Clinical Symposium (RWCS).

“There’s a lesson here,” said Eric M. Ruderman, MD, professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University Feinberg School of Medicine, Chicago, Illinois. “We’ve spent a lot of time working with the dermatologists in the last 10 years to try to coordinate what we’re doing [for psoriatic disease]. It’s time to start working with the gastroenterologists more.”

Ruderman_Eric_M_IL_3_web.jpg

The findings offer “more evidence” for an increasingly documented overlap of IBD with SpA — whether axial or peripheral — and suggest there is underdiagnosis of SpA among patients with IBD. “It’s important,” he said at the meeting, “because if there are meaningful joint symptoms, this should be considered when making treatment choices [for IBD],” just as rheumatologists must be aware of the potential for IBD in choosing therapies.

Dr. Ruderman also urged rheumatologists making treatment decisions for axSpA to more carefully consider the role of central pain in driving residual symptoms in patients on biologic disease-modifying antirheumatic drugs (bDMARDs). He pointed to a 2023 study of patients with radiographic axSpA (r-axSpA) receiving bDMARDs that showed significant associations between high central pain and a greater odds of having higher disease activity, independent of elevated C-reactive protein (CRP) levels.

“I’ve come to the conclusion that there’s a huge amount of central pain in our patients — that it [affects] 20%-30% of our patients, no matter what rheumatologic disease they have,” he said, “and if you don’t acknowledge and consider that, you’ll keep churning through medications that aren’t going to work because you’re not addressing a fundamental issue.”

Among other key studies of 2023 highlighted by Dr. Ruderman was a large retrospective cohort study showing a similar incidence of ankylosing spondylitis (AS) in US military men and women screened for chronic back pain and the GO-BACK withdrawal and retreatment trial of golimumab suggesting that dosing can be extended.

Meanwhile, last year brought more bad news for interleukin (IL)-23 inhibition in axSpA, with the termination of a phase 2 study of tildrakizumab (Ilumya). Good news came with the US Food and Drug Administration approval in 2023 of an intravenous formulation of the IL-17 inhibitor secukinumab (Cosentyx), which will be helpful for some Medicare patients. And moving forward, the biologic pipeline is SpA is “almost all about new pathways in the IL-17 arena,” Dr. Ruderman said.

Making Good Drug Choices for the Gut and the Joints

In the study of SpA among patients with IBD, reported at the EULAR 2023 meeting in Milan, Italy, rheumatologists assessed 110 consecutive patients — 34% of whom were diagnosed with Crohn’s disease and 59% of whom had ulcerative colitis — from a Danish IBD inception cohort. The patients, about 40% of whom were male, had a mean age of 42.

At the time of IBD diagnosis, 49% had arthralgias/musculoskeletal symptoms, 52% fulfilled Assessment of SpondyloArthritis International Society (ASAS) classification criteria for peripheral SpA, and 49% had synovitis and/or enthesitis verified by ultrasound, Dr. Ruderman said.

Gastroenterologists like the integrin antagonist vedolizumab (Entyvio) for some patients with IBD because “it’s a very gut-specific drug and doesn’t have as much impact on the systemic immune system as other drugs, but because it’s gut specific, it does nothing for peripheral or axial joint symptoms,” Dr. Ruderman said in an interview after the meeting. “We’ve seen patients switched to this drug from Humira [or other biologics] and suddenly they have joint pains they never had before.”

The IL-12/23 inhibitor ustekinumab (Stelara) and the IL-23 inhibitor risankizumab (Skyrizi) are also sometimes selected for IBD, but “neither work well for patients with confirmed axSpA or inflammatory axial spine pain and arthritis,” he said. “Maybe these patients belong on a TNF [tumor necrosis factor] inhibitor or a JAK [Janus kinase] inhibitor, which will manage both the joints and the gut.”

“It’s not that we don’t talk to one another, but as we get more and more drugs in this space — both us and the gastroenterologists — it behooves us to communicate better to make sure we’re making the right choices for patients,” Dr. Ruderman said in the interview.

On the flip side, there’s a clear link between patients with axSpA who have or later develop IBD, as was further documented in 2023 by a multicenter Spanish study that evaluated patients with SpA (including both radiographic and nonradiographic axSpA) for the prevalence of undiagnosed IBD, Dr. Ruderman said at the RWCS.

The study, reported at the American College of Rheumatology (ACR) 2023 annual meeting, included only patients who were bDAMRD-naive and off of steroids for at least 30 days. The researchers used elevated fecal calprotectin levels (≥ 80 mcg/g) followed by colonoscopy — and an endoscopic capsule study or MRI if colonoscopy was normal — to confirm a diagnosis of IBD. Of 559 patients, 4.4% had such a confirmed diagnosis (95% with Crohn’s disease), and interestingly, only 30% of these patients had clinical IBD symptoms.

“These are people who had no suspicion,” Dr. Ruderman said at the meeting. “You could say that maybe not having symptoms is not a big deal, but over time, maybe there will be consequences.”

The IL-17 inhibitors ixekizumab (Taltz), secukinumab, and bimekizumab (Bimzelx) are generally felt to be contraindicated in patients who have confirmed IBD, Dr. Ruderman noted in the interview. “While we don’t want to necessarily avoid those drugs, we need to be aware of the potential [for IBD],” he said, “and we need to have a low threshold of suspicion if our patients develop any GI symptoms.”

Considering Noninflammatory Residual Pain

The 2023 central pain study that caught Dr. Ruderman’s attention — research reported at the EULAR 2023 meeting — looked at 70 patients with r-axSpA receiving bDMARD treatment (mostly TNF inhibitors) who were being followed in an extension of the German Spondyloarthritis Inception Cohort. Investigators used the Widespread Pain Index (WPI) to help quantify central pain/central sensitization and the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) to measure disease activity.

“Central pain was actually associated with having residual symptoms,” Dr. Ruderman said at the RWCS. Higher WPI scores were significantly associated with higher ASDAS-CRP scores, and a high WPI was also associated with higher odds of having high or very high disease activity (ASDAS > 2.1), independent of other factors including elevated CRP, the investigators reported in their abstract.

Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, commented that “we don’t have great [non-opioid] treatments for pain,” prompting Dr. Ruderman to emphasize the importance of “resisting the urge to [automatically] switch to another biologic” without trying to discern whether residual pain is inflammatory or noninflammatory in nature.

“I’m really comfortable with this,” Dr. Ruderman said, noting that he prescribes drugs like duloxetine or pregabalin for suspected central pain. “For the statin (for cardiovascular disease prevention), I’m more likely to turn back to the primary care physician and work with them, but here it’s part of what we’re treating — it becomes part of our tool kits.”

The central pain issue, Dr. Ruderman said after the meeting, is one of recognition and nomenclature. In the last few years, “there’s been a tendency to get away from secondary fibromyalgia as a label. There’s a lot of baggage with the diagnosis, unfortunately,” he said in the interview. “And it’s all connected. … It’s very likely that the [central] pain signaling is triggered by the inflammatory pain in the first place.”

A New Look at Sex-Specific Incidence of AS

The study on AS in a retrospective cohort of 729,000 working-age US military service members “flew under the radar,” but its finding of a similar incidence in men and women who underwent screening for chronic back pain is “fascinating,” Dr. Ruderman said. Compared with females, men were not significantly more likely to have a diagnosis of AS (adjusted odds ratio [OR], 0.79; 95% CI, 0.61-1.02; P = .072), the researchers reported.

“We’ve always assumed that AS is a male disease, and that, as we got into nonradiographic axSpA, we would see more women. This study calls that into question,” he said.

More Light on bDMARD Dosage Extension and Withdrawal

The GO-BACK study of the TNF inhibitor golimumab (Simponi) randomized 188 patients with inactive nonradiographic axSpA after 6 months of 50 mg golimumab monthly to treatment withdrawal/monthly placebo, continued monthly treatment, or treatment every 2 months. The take-home message, Dr. Ruderman said, is that “withdrawal, but not reduction in dose, led to a higher risk of flare.”

Also notable in this study published in 2023 is that “almost 100% of those who flared were recaptured with the reinitiation of monthly dosing,” he said. “So you don’t lose if you try to stop … [although] I don’t think that will ever be a successful strategy.” (The proportion of patients without a disease flare over 12 months was 34% in the withdrawal group, 68% in the extended dosing group, and 84% in the continued monthly treatment group.)

Dosing extensions have been shown to be potentially viable with other biologics, “but with this one, it looks like you can spread it out almost with impunity because it doesn’t look like there’s much difference” between continuing monthly and extending, Dr. Kavanaugh commented.

Another study from 2023 of the IL-17A inhibitor ixekizumab in axSpA similarly showed a high recapture rate for patients who withdrew from therapy and then flared. In this phase 3 extension study in which 155 patients with inactive or low-level disease were randomized at week 24 to continued ixekizumab or placebo, 53% of placebo patients flared by 2 years, compared with 13% in the ixekizumab arm. Of those who flared, 96% recaptured low disease activity with re-initiation of therapy.

“It’s the same story. You might get away with [stopping the therapy] because it’s not 100% who flared. But is it worth it?” Dr. Ruderman said.

IL-23 Inhibition in Axial Disease and the Pipeline

Is the chapter on IL-23 inhibitors closed for axSpA? Aside from a possible role for axial disease in psoriatic arthritis (PsA), it likely is, Dr. Ruderman said, pointing to the phase 2 randomized, double-blind, placebo-controlled study of tildrakizumab in patients with AS that was terminated at week 24 after the drug showed no difference in efficacy from placebo.

Dr. Kavanaugh agreed. “This adds to the data on risankizumab and ustekinumab in studies done properly in AS,” he said. “There’s no benefit.”

The “real issue” still to be determined, said Dr. Ruderman, “is what is the role of IL-23 inhibitors in patients with axial PsA?”

A post-hoc analysis of data from the SELECT PsA 1 and 2 trials, published in 2023, showed greater improvement in the overall Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score in patients with axial disease who received 15 mg upadacitinib (Rinvoq), compared with placebo.

“It suggests there’s improvement in the patients with axial PsA as defined [by a high BASDAI score], but they didn’t compare this with patients without axial disease … it’s muddy,” Dr. Ruderman said. Other research that’s underway should provide clarity, Dr. Kavanaugh said.

The pipeline for new treatments for SpA, including axSpA, is focused on new biologics targeting the IL-17 pathways, as well as a fair number of targeted synthetics, Dr. Ruderman said. “What will be interesting to me is what happens with the TYK2 inhibitors … because one of the postulated mechanisms is that the IL-23 signals through TYK-2,” he said. “So if that’s the mechanism, will they really help our patients with axial disease? We need the trials to find out.”

The intravenous formulation of secukinumab, approved in 2023 for AS, nr-axSpA, and PsA, is a “nice addition to our armamentarium, Dr. Ruderman noted in his 2023 review. “For years, a patient doing well on an IL-17 inhibitor for their axial disease or their psoriatic disease would hit Medicare age and suddenly couldn’t afford subcutaneous administration, and we had to switch them over to an IV-TNF inhibitor,” he said. “Now we have an IV IL-17 inhibitor.”