Rheumatology News

WASHINGTON — New draft guidance on the use of musculoskeletal ultrasound (MSUS) for diagnosis, monitoring, and prognosis of psoriatic arthritis was presented at the American College of Rheumatology (ACR) 2024 Annual Meeting. The new recommendations, intended to update 2012 guidance on rheumatologic use of MSUS, will go through another round of expert committee voting before being finalized and published.

“Even in the last 12 years, we’ve seen substantive advances, and there’s been significant improvements in musculoskeletal ultrasound technology,” Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program, told attendees. She noted that more than 30,000 articles on MSUS and arthritis have been published since the 2012 guidance. “We’ve seen mastery in teaching and really a wide distribution of this education to the next generation of rheumatologists, and this has led to significant increases in the use of musculoskeletal ultrasound in clinical practices.” 

She also noted there have been significant improvements in therapeutic agents and strategies in psoriatic arthritis medications and that differences in today’s patients compared with those of a decade ago have influenced clinical questions related to the use of MSUS in rheumatology. 

To develop the guidelines, a committee identified key domains and relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). A review of the literature published since 1993 in PubMed, Embase, and the Cochrane Database provided the evidence base, and a committee of 11 experts voted on the strength of the evidence for 22 statements. They rejected two that lacked consensus, and another round of voting will occur before the guidance is published. 

Michael Stein, MD, assistant professor of medicine in rheumatology at McGill University in Montreal, Quebec, Canada, who was not involved in the guidance development, said he hopes and expects this new guidance will help persuade more clinicians to recognize the value of using MSUS in their practice. 

“Number one, it’ll highlight the huge amount of data that exist that support using this technology for managing these groups of patients, among others, and I think it’ll also highlight the enormous number of questions that still exist that will hopefully be answered in the future, promoting new research,” Stein told this news organization. 

“I do think it does allow people who are not comfortable with technology to adopt technology in a very gradual way and make it less threatening,” Stein added. 

“Ultrasound is becoming part of the landscape, and so increasingly, we’re trying to promote it as being part of the standard of care, or at least an adjunct to care. I commend the committee for doing all this amazing work.” 

 

Predicting and Diagnosing Early Psoriatic Arthritis

Catherine J. Bakewell, MD, a rheumatologist at Intermountain Health in Salt Lake City, Utah, reviewed the committee’s statements, starting with strong consensus that MSUS can help with diagnosing early psoriatic arthritis. Evidence has shown that patients with psoriasis who have subclinical synovitis, enthesitis, and other features have gone on to develop psoriatic arthritis, and researchers have documented the transition with ultrasonography. 

“We can use it to enhance our CASPAR classification criteria” by using ultrasound to change how clinicians apply the classification criteria, Bakewell said. “For example, in order to go through those classification criteria, a patient has to have confirmed inflammatory articular disease, either the joint synthesis or spine, and ultrasound can help clarify that state for us.” 

She also noted the potential for ultrasonography to help as a screening tool because studies have suggested that dermatologists’ use of handheld ultrasound transducers can help in screening appropriate patients to refer to rheumatologists. 

Patients with psoriasis being evaluated for a potential early psoriatic arthritis diagnosis should undergo MSUS of the bilateral quadriceps tendon, patellar ligament, Achilles tendon, and plantar fascia entheses at a minimum, per moderate consensus. 

“This truly is just designed to be the highest bang for your buck. This is designed for clinicians in practice,” Bakewell said. She noted criticism about the exclusion of upper extremities — something that will be discussed in the future published paper — but one reason that was excluded is because common findings have occurred in healthy individuals in some areas. 

Moderate consensus also supported reliance on entheseal features — including hypoechogenicity, thickening, Doppler signal, bone erosions, enthesophytes/calcifications, and bursal enlargement — to support a diagnosis. Interpretation of entheseal changes in patients with psoriasis should take into account characteristics such as age, body mass index (BMI), and biomechanical stress.

“There are numerous articles already existing pointing out that people who are over the age of 50 with a BMI over 30 kg/m2 or who have higher levels of biomechanical stress will score more highly on endocytoscoring systems, even in the absence of an underlying disorder,” Bakewell said. Among the mitigating strategies proposed in the literature are to have at least three positive sites to qualify for an indication or to look at the specificity of each elementary lesion. “Whatever mitigating strategy the clinician chooses to use, they need to bear in mind some of these features are not exclusive to spondyloarthritis,” she said. “It has to be taken in the clinical context.” 

Scanning the hand, wrist, foot, and relevant symptomatic joints with MSUS to diagnose early psoriatic arthritis in patients with psoriasis received strong consensus. Intracapsular findings of synovitis and erosions may help support an early diagnosis in patients with psoriasis. “These are not obviously specific to psoriatic arthritis but support the diagnosis” with moderate consensus, Bakewell said. “The more specific findings are these extracapsular findings — which did attain a strong level of consensus — which are enthesitis, tenosynovitis, and dactylitis, all supporting that diagnosis of early psoriatic arthritis.” 

For patients with psoriatic arthritis, the cutoff for defining a positive joint received moderate consensus for grayscale (GS) of at least 2 or at least 1 with power Doppler (PD) of at least 1. 

Strong consensus supported confirming the presence of dactylitis in patients with psoriasis or psoriatic arthritis through a combination of features including tenosynovitis, subcutaneous edema, soft tissue thickening, synovitis, paratenonitis, and pulley thickening. 

“I will also note that enthesitis is missing from this definition of dactylitis,” Bakewell said. “It is, however, a feature that is detectable with those higher-frequency transducers, but this is a relatively early area of research and did not make it into this guidance statement.” 

Moderate consensus supported determination of an increased risk of radiographic erosions in patients with a dactylitis PD score of at least 1. 

“We know as far back as 2005, Brockbank et al taught us that the dactylitic digit is associated with radiographic erosion in that particular digit,” Bakewell said. “Flash forward all the way to 2021: Dubash et al published the paper, ‘Dactylitis is an indicator of a more severe phenotype independently associated with greater swollen joint counts, C-reactive protein, ultrasound synovitis, and erosive damage,’ showing us that this is more than just that particular digit. It is a more severe phenotype, and very minimal Doppler signal, just 1+, is associated with erosive damage.”

 

Progression of Psoriatic Arthritis and Shared Decision-Making

Strong consensus existed for all statements related to progression of psoriatic arthritis and the role of MSUS in shared decision-making. The first is that synovitis and enthesitis in MSUS can predict radiographic progression and worsening of patient-related outcomes. Second, sonographic features — including increased Doppler signal in synovitis, enthesitis, and tenosynovitis — and presence of bone erosions and dactylitis can help inform decisions regarding therapy escalation.

“This is the first treatment management–specific statement we have made, but we feel this to be justified because each of these ultrasonographic features is associated with overall inflammatory burden and worse outcomes, be it health assessment questionnaires, disability index, or patient-reported outcomes to harder endpoints, such as radiographic erosions or relapse of clinical remission,” Bakewell said. 

Finally, MSUS can help inform patients of their disease activity to assist in shared decision-making regarding escalation or de-escalation of therapy.

“We’ve all had this in our practices. You’ve had the patient in front of you who is very inflamed, and they say, ‘Doctor, can’t I please use doTERRA oils? Do I really need to go on one of these toxic drugs? I’ve read the package insert,’” Bakewell said. “Aside from having that conversation about the relative risk–benefit of any individual medication that you recommend, it’s helpful to put the ultrasound transducer on the patient, show them the fire of the Doppler, show them the erosion, show them the damage that is being done. It comes to life for them, especially if they’re not suffering that much with pain or stiffness.” 

Bakewell also addressed patients at the other end of the pain spectrum who are suffering more. “You’ve also probably had the patient with psoriatic arthritis and fibromyalgia who comes in and tells you, ‘Doctor, my psoriatic arthritis has been terrible. I’m flaring. I need more immune-suppressing medication,’” she said. “Their exam looks pretty good, and it’s helpful to put that transducer on them and show them the absence of Doppler signal, show them that you’re taking them very seriously. You didn’t just squeeze them and say they’re fine, but you looked more deeply. You looked underneath the skin, and that helps with that patient–provider understanding and communication. I use this every day.” 

 

Clarifying Disease State and Defining Remission

As with patients with psoriasis undergoing evaluation, there was strong consensus for interpreting entheseal changes in psoriatic arthritis in the context of patient characteristics such as age, BMI, and biomechanical stress.

There was moderate consensus for confirming psoriatic arthritis flare with MSUS. Bakewell noted that many have seen in their practices how physical exams can be misleading, such as when a patient appears clinically normal but has ongoing synovitis, or on the flip side, the patient has a swollen joint but nothing is lighting up with Doppler on the ultrasound.

All of the statements on MSUS for remission received moderate consensus. These included defining MSUS remission as a PD score of 0 in entheses and synovial tissues and defining ultrasonographic remission as a total PD ultrasound score of 0, summing all analyzed joints and entheses, at a single given time point.

When using MSUS to evaluate for remission, it’s reasonable to screen the lower-extremity entheses, wrists, metacarpophalangeal joints, interphalangeal hand joints, metatarsophalangeal joints, and relevant symptomatic joints. The inflammatory features to evaluate to confirm ultrasound-defined remission include PD enthesitis, GS and PD synovitis, tenosynovitis, and dactylitis. Finally, for those in remission, subclinical inflammation detected by MSUS likely predicts a higher rate of flare. 

During the discussion, Bakewell reiterated that MSUS should be regarded as a tool for patient subsets who can benefit from its use, rather than being used routinely across large patient groups without a clear purpose. “It’s used to answer a question,” she said. “If you’re going to demonstrate the efficacy of a tool, you have to use it appropriately, aka when there’s a question. We don’t need to ultrasound every patient every visit.”

No external funding for the development of the guidance was noted. Ranganath has reported receiving research support from Bristol Myers Squibb and Mallinckrodt. Bakewell has reported receiving speaking/consulting fees from AbbVie, UCB, Lilly, Janssen, Novartis, Sanofi/Regeneron/Genzyme, and Pfizer. Stein had no disclosures. 

 

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

WASHINGTON — New draft guidance on the use of musculoskeletal ultrasound (MSUS) for diagnosis, monitoring, and prognosis of psoriatic arthritis was presented at the American College of Rheumatology (ACR) 2024 Annual Meeting. The new recommendations, intended to update 2012 guidance on rheumatologic use of MSUS, will go through another round of expert committee voting before being finalized and published.

“Even in the last 12 years, we’ve seen substantive advances, and there’s been significant improvements in musculoskeletal ultrasound technology,” Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program, told attendees. She noted that more than 30,000 articles on MSUS and arthritis have been published since the 2012 guidance. “We’ve seen mastery in teaching and really a wide distribution of this education to the next generation of rheumatologists, and this has led to significant increases in the use of musculoskeletal ultrasound in clinical practices.” 

She also noted there have been significant improvements in therapeutic agents and strategies in psoriatic arthritis medications and that differences in today’s patients compared with those of a decade ago have influenced clinical questions related to the use of MSUS in rheumatology. 

To develop the guidelines, a committee identified key domains and relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). A review of the literature published since 1993 in PubMed, Embase, and the Cochrane Database provided the evidence base, and a committee of 11 experts voted on the strength of the evidence for 22 statements. They rejected two that lacked consensus, and another round of voting will occur before the guidance is published. 

Michael Stein, MD, assistant professor of medicine in rheumatology at McGill University in Montreal, Quebec, Canada, who was not involved in the guidance development, said he hopes and expects this new guidance will help persuade more clinicians to recognize the value of using MSUS in their practice. 

“Number one, it’ll highlight the huge amount of data that exist that support using this technology for managing these groups of patients, among others, and I think it’ll also highlight the enormous number of questions that still exist that will hopefully be answered in the future, promoting new research,” Stein told this news organization. 

“I do think it does allow people who are not comfortable with technology to adopt technology in a very gradual way and make it less threatening,” Stein added. 

“Ultrasound is becoming part of the landscape, and so increasingly, we’re trying to promote it as being part of the standard of care, or at least an adjunct to care. I commend the committee for doing all this amazing work.” 

 

Predicting and Diagnosing Early Psoriatic Arthritis

Catherine J. Bakewell, MD, a rheumatologist at Intermountain Health in Salt Lake City, Utah, reviewed the committee’s statements, starting with strong consensus that MSUS can help with diagnosing early psoriatic arthritis. Evidence has shown that patients with psoriasis who have subclinical synovitis, enthesitis, and other features have gone on to develop psoriatic arthritis, and researchers have documented the transition with ultrasonography. 

“We can use it to enhance our CASPAR classification criteria” by using ultrasound to change how clinicians apply the classification criteria, Bakewell said. “For example, in order to go through those classification criteria, a patient has to have confirmed inflammatory articular disease, either the joint synthesis or spine, and ultrasound can help clarify that state for us.” 

She also noted the potential for ultrasonography to help as a screening tool because studies have suggested that dermatologists’ use of handheld ultrasound transducers can help in screening appropriate patients to refer to rheumatologists. 

Patients with psoriasis being evaluated for a potential early psoriatic arthritis diagnosis should undergo MSUS of the bilateral quadriceps tendon, patellar ligament, Achilles tendon, and plantar fascia entheses at a minimum, per moderate consensus. 

“This truly is just designed to be the highest bang for your buck. This is designed for clinicians in practice,” Bakewell said. She noted criticism about the exclusion of upper extremities — something that will be discussed in the future published paper — but one reason that was excluded is because common findings have occurred in healthy individuals in some areas. 

Moderate consensus also supported reliance on entheseal features — including hypoechogenicity, thickening, Doppler signal, bone erosions, enthesophytes/calcifications, and bursal enlargement — to support a diagnosis. Interpretation of entheseal changes in patients with psoriasis should take into account characteristics such as age, body mass index (BMI), and biomechanical stress.

“There are numerous articles already existing pointing out that people who are over the age of 50 with a BMI over 30 kg/m2 or who have higher levels of biomechanical stress will score more highly on endocytoscoring systems, even in the absence of an underlying disorder,” Bakewell said. Among the mitigating strategies proposed in the literature are to have at least three positive sites to qualify for an indication or to look at the specificity of each elementary lesion. “Whatever mitigating strategy the clinician chooses to use, they need to bear in mind some of these features are not exclusive to spondyloarthritis,” she said. “It has to be taken in the clinical context.” 

Scanning the hand, wrist, foot, and relevant symptomatic joints with MSUS to diagnose early psoriatic arthritis in patients with psoriasis received strong consensus. Intracapsular findings of synovitis and erosions may help support an early diagnosis in patients with psoriasis. “These are not obviously specific to psoriatic arthritis but support the diagnosis” with moderate consensus, Bakewell said. “The more specific findings are these extracapsular findings — which did attain a strong level of consensus — which are enthesitis, tenosynovitis, and dactylitis, all supporting that diagnosis of early psoriatic arthritis.” 

For patients with psoriatic arthritis, the cutoff for defining a positive joint received moderate consensus for grayscale (GS) of at least 2 or at least 1 with power Doppler (PD) of at least 1. 

Strong consensus supported confirming the presence of dactylitis in patients with psoriasis or psoriatic arthritis through a combination of features including tenosynovitis, subcutaneous edema, soft tissue thickening, synovitis, paratenonitis, and pulley thickening. 

“I will also note that enthesitis is missing from this definition of dactylitis,” Bakewell said. “It is, however, a feature that is detectable with those higher-frequency transducers, but this is a relatively early area of research and did not make it into this guidance statement.” 

Moderate consensus supported determination of an increased risk of radiographic erosions in patients with a dactylitis PD score of at least 1. 

“We know as far back as 2005, Brockbank et al taught us that the dactylitic digit is associated with radiographic erosion in that particular digit,” Bakewell said. “Flash forward all the way to 2021: Dubash et al published the paper, ‘Dactylitis is an indicator of a more severe phenotype independently associated with greater swollen joint counts, C-reactive protein, ultrasound synovitis, and erosive damage,’ showing us that this is more than just that particular digit. It is a more severe phenotype, and very minimal Doppler signal, just 1+, is associated with erosive damage.”

 

Progression of Psoriatic Arthritis and Shared Decision-Making

Strong consensus existed for all statements related to progression of psoriatic arthritis and the role of MSUS in shared decision-making. The first is that synovitis and enthesitis in MSUS can predict radiographic progression and worsening of patient-related outcomes. Second, sonographic features — including increased Doppler signal in synovitis, enthesitis, and tenosynovitis — and presence of bone erosions and dactylitis can help inform decisions regarding therapy escalation.

“This is the first treatment management–specific statement we have made, but we feel this to be justified because each of these ultrasonographic features is associated with overall inflammatory burden and worse outcomes, be it health assessment questionnaires, disability index, or patient-reported outcomes to harder endpoints, such as radiographic erosions or relapse of clinical remission,” Bakewell said. 

Finally, MSUS can help inform patients of their disease activity to assist in shared decision-making regarding escalation or de-escalation of therapy.

“We’ve all had this in our practices. You’ve had the patient in front of you who is very inflamed, and they say, ‘Doctor, can’t I please use doTERRA oils? Do I really need to go on one of these toxic drugs? I’ve read the package insert,’” Bakewell said. “Aside from having that conversation about the relative risk–benefit of any individual medication that you recommend, it’s helpful to put the ultrasound transducer on the patient, show them the fire of the Doppler, show them the erosion, show them the damage that is being done. It comes to life for them, especially if they’re not suffering that much with pain or stiffness.” 

Bakewell also addressed patients at the other end of the pain spectrum who are suffering more. “You’ve also probably had the patient with psoriatic arthritis and fibromyalgia who comes in and tells you, ‘Doctor, my psoriatic arthritis has been terrible. I’m flaring. I need more immune-suppressing medication,’” she said. “Their exam looks pretty good, and it’s helpful to put that transducer on them and show them the absence of Doppler signal, show them that you’re taking them very seriously. You didn’t just squeeze them and say they’re fine, but you looked more deeply. You looked underneath the skin, and that helps with that patient–provider understanding and communication. I use this every day.” 

 

Clarifying Disease State and Defining Remission

As with patients with psoriasis undergoing evaluation, there was strong consensus for interpreting entheseal changes in psoriatic arthritis in the context of patient characteristics such as age, BMI, and biomechanical stress.

There was moderate consensus for confirming psoriatic arthritis flare with MSUS. Bakewell noted that many have seen in their practices how physical exams can be misleading, such as when a patient appears clinically normal but has ongoing synovitis, or on the flip side, the patient has a swollen joint but nothing is lighting up with Doppler on the ultrasound.

All of the statements on MSUS for remission received moderate consensus. These included defining MSUS remission as a PD score of 0 in entheses and synovial tissues and defining ultrasonographic remission as a total PD ultrasound score of 0, summing all analyzed joints and entheses, at a single given time point.

When using MSUS to evaluate for remission, it’s reasonable to screen the lower-extremity entheses, wrists, metacarpophalangeal joints, interphalangeal hand joints, metatarsophalangeal joints, and relevant symptomatic joints. The inflammatory features to evaluate to confirm ultrasound-defined remission include PD enthesitis, GS and PD synovitis, tenosynovitis, and dactylitis. Finally, for those in remission, subclinical inflammation detected by MSUS likely predicts a higher rate of flare. 

During the discussion, Bakewell reiterated that MSUS should be regarded as a tool for patient subsets who can benefit from its use, rather than being used routinely across large patient groups without a clear purpose. “It’s used to answer a question,” she said. “If you’re going to demonstrate the efficacy of a tool, you have to use it appropriately, aka when there’s a question. We don’t need to ultrasound every patient every visit.”

No external funding for the development of the guidance was noted. Ranganath has reported receiving research support from Bristol Myers Squibb and Mallinckrodt. Bakewell has reported receiving speaking/consulting fees from AbbVie, UCB, Lilly, Janssen, Novartis, Sanofi/Regeneron/Genzyme, and Pfizer. Stein had no disclosures. 

 

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

WASHINGTON — New draft guidance on the use of musculoskeletal ultrasound (MSUS) for diagnosis, monitoring, and prognosis of psoriatic arthritis was presented at the American College of Rheumatology (ACR) 2024 Annual Meeting. The new recommendations, intended to update 2012 guidance on rheumatologic use of MSUS, will go through another round of expert committee voting before being finalized and published.

“Even in the last 12 years, we’ve seen substantive advances, and there’s been significant improvements in musculoskeletal ultrasound technology,” Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program, told attendees. She noted that more than 30,000 articles on MSUS and arthritis have been published since the 2012 guidance. “We’ve seen mastery in teaching and really a wide distribution of this education to the next generation of rheumatologists, and this has led to significant increases in the use of musculoskeletal ultrasound in clinical practices.” 

She also noted there have been significant improvements in therapeutic agents and strategies in psoriatic arthritis medications and that differences in today’s patients compared with those of a decade ago have influenced clinical questions related to the use of MSUS in rheumatology. 

To develop the guidelines, a committee identified key domains and relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). A review of the literature published since 1993 in PubMed, Embase, and the Cochrane Database provided the evidence base, and a committee of 11 experts voted on the strength of the evidence for 22 statements. They rejected two that lacked consensus, and another round of voting will occur before the guidance is published. 

Michael Stein, MD, assistant professor of medicine in rheumatology at McGill University in Montreal, Quebec, Canada, who was not involved in the guidance development, said he hopes and expects this new guidance will help persuade more clinicians to recognize the value of using MSUS in their practice. 

“Number one, it’ll highlight the huge amount of data that exist that support using this technology for managing these groups of patients, among others, and I think it’ll also highlight the enormous number of questions that still exist that will hopefully be answered in the future, promoting new research,” Stein told this news organization. 

“I do think it does allow people who are not comfortable with technology to adopt technology in a very gradual way and make it less threatening,” Stein added. 

“Ultrasound is becoming part of the landscape, and so increasingly, we’re trying to promote it as being part of the standard of care, or at least an adjunct to care. I commend the committee for doing all this amazing work.” 

 

Predicting and Diagnosing Early Psoriatic Arthritis

Catherine J. Bakewell, MD, a rheumatologist at Intermountain Health in Salt Lake City, Utah, reviewed the committee’s statements, starting with strong consensus that MSUS can help with diagnosing early psoriatic arthritis. Evidence has shown that patients with psoriasis who have subclinical synovitis, enthesitis, and other features have gone on to develop psoriatic arthritis, and researchers have documented the transition with ultrasonography. 

“We can use it to enhance our CASPAR classification criteria” by using ultrasound to change how clinicians apply the classification criteria, Bakewell said. “For example, in order to go through those classification criteria, a patient has to have confirmed inflammatory articular disease, either the joint synthesis or spine, and ultrasound can help clarify that state for us.” 

She also noted the potential for ultrasonography to help as a screening tool because studies have suggested that dermatologists’ use of handheld ultrasound transducers can help in screening appropriate patients to refer to rheumatologists. 

Patients with psoriasis being evaluated for a potential early psoriatic arthritis diagnosis should undergo MSUS of the bilateral quadriceps tendon, patellar ligament, Achilles tendon, and plantar fascia entheses at a minimum, per moderate consensus. 

“This truly is just designed to be the highest bang for your buck. This is designed for clinicians in practice,” Bakewell said. She noted criticism about the exclusion of upper extremities — something that will be discussed in the future published paper — but one reason that was excluded is because common findings have occurred in healthy individuals in some areas. 

Moderate consensus also supported reliance on entheseal features — including hypoechogenicity, thickening, Doppler signal, bone erosions, enthesophytes/calcifications, and bursal enlargement — to support a diagnosis. Interpretation of entheseal changes in patients with psoriasis should take into account characteristics such as age, body mass index (BMI), and biomechanical stress.

“There are numerous articles already existing pointing out that people who are over the age of 50 with a BMI over 30 kg/m2 or who have higher levels of biomechanical stress will score more highly on endocytoscoring systems, even in the absence of an underlying disorder,” Bakewell said. Among the mitigating strategies proposed in the literature are to have at least three positive sites to qualify for an indication or to look at the specificity of each elementary lesion. “Whatever mitigating strategy the clinician chooses to use, they need to bear in mind some of these features are not exclusive to spondyloarthritis,” she said. “It has to be taken in the clinical context.” 

Scanning the hand, wrist, foot, and relevant symptomatic joints with MSUS to diagnose early psoriatic arthritis in patients with psoriasis received strong consensus. Intracapsular findings of synovitis and erosions may help support an early diagnosis in patients with psoriasis. “These are not obviously specific to psoriatic arthritis but support the diagnosis” with moderate consensus, Bakewell said. “The more specific findings are these extracapsular findings — which did attain a strong level of consensus — which are enthesitis, tenosynovitis, and dactylitis, all supporting that diagnosis of early psoriatic arthritis.” 

For patients with psoriatic arthritis, the cutoff for defining a positive joint received moderate consensus for grayscale (GS) of at least 2 or at least 1 with power Doppler (PD) of at least 1. 

Strong consensus supported confirming the presence of dactylitis in patients with psoriasis or psoriatic arthritis through a combination of features including tenosynovitis, subcutaneous edema, soft tissue thickening, synovitis, paratenonitis, and pulley thickening. 

“I will also note that enthesitis is missing from this definition of dactylitis,” Bakewell said. “It is, however, a feature that is detectable with those higher-frequency transducers, but this is a relatively early area of research and did not make it into this guidance statement.” 

Moderate consensus supported determination of an increased risk of radiographic erosions in patients with a dactylitis PD score of at least 1. 

“We know as far back as 2005, Brockbank et al taught us that the dactylitic digit is associated with radiographic erosion in that particular digit,” Bakewell said. “Flash forward all the way to 2021: Dubash et al published the paper, ‘Dactylitis is an indicator of a more severe phenotype independently associated with greater swollen joint counts, C-reactive protein, ultrasound synovitis, and erosive damage,’ showing us that this is more than just that particular digit. It is a more severe phenotype, and very minimal Doppler signal, just 1+, is associated with erosive damage.”

 

Progression of Psoriatic Arthritis and Shared Decision-Making

Strong consensus existed for all statements related to progression of psoriatic arthritis and the role of MSUS in shared decision-making. The first is that synovitis and enthesitis in MSUS can predict radiographic progression and worsening of patient-related outcomes. Second, sonographic features — including increased Doppler signal in synovitis, enthesitis, and tenosynovitis — and presence of bone erosions and dactylitis can help inform decisions regarding therapy escalation.

“This is the first treatment management–specific statement we have made, but we feel this to be justified because each of these ultrasonographic features is associated with overall inflammatory burden and worse outcomes, be it health assessment questionnaires, disability index, or patient-reported outcomes to harder endpoints, such as radiographic erosions or relapse of clinical remission,” Bakewell said. 

Finally, MSUS can help inform patients of their disease activity to assist in shared decision-making regarding escalation or de-escalation of therapy.

“We’ve all had this in our practices. You’ve had the patient in front of you who is very inflamed, and they say, ‘Doctor, can’t I please use doTERRA oils? Do I really need to go on one of these toxic drugs? I’ve read the package insert,’” Bakewell said. “Aside from having that conversation about the relative risk–benefit of any individual medication that you recommend, it’s helpful to put the ultrasound transducer on the patient, show them the fire of the Doppler, show them the erosion, show them the damage that is being done. It comes to life for them, especially if they’re not suffering that much with pain or stiffness.” 

Bakewell also addressed patients at the other end of the pain spectrum who are suffering more. “You’ve also probably had the patient with psoriatic arthritis and fibromyalgia who comes in and tells you, ‘Doctor, my psoriatic arthritis has been terrible. I’m flaring. I need more immune-suppressing medication,’” she said. “Their exam looks pretty good, and it’s helpful to put that transducer on them and show them the absence of Doppler signal, show them that you’re taking them very seriously. You didn’t just squeeze them and say they’re fine, but you looked more deeply. You looked underneath the skin, and that helps with that patient–provider understanding and communication. I use this every day.” 

 

Clarifying Disease State and Defining Remission

As with patients with psoriasis undergoing evaluation, there was strong consensus for interpreting entheseal changes in psoriatic arthritis in the context of patient characteristics such as age, BMI, and biomechanical stress.

There was moderate consensus for confirming psoriatic arthritis flare with MSUS. Bakewell noted that many have seen in their practices how physical exams can be misleading, such as when a patient appears clinically normal but has ongoing synovitis, or on the flip side, the patient has a swollen joint but nothing is lighting up with Doppler on the ultrasound.

All of the statements on MSUS for remission received moderate consensus. These included defining MSUS remission as a PD score of 0 in entheses and synovial tissues and defining ultrasonographic remission as a total PD ultrasound score of 0, summing all analyzed joints and entheses, at a single given time point.

When using MSUS to evaluate for remission, it’s reasonable to screen the lower-extremity entheses, wrists, metacarpophalangeal joints, interphalangeal hand joints, metatarsophalangeal joints, and relevant symptomatic joints. The inflammatory features to evaluate to confirm ultrasound-defined remission include PD enthesitis, GS and PD synovitis, tenosynovitis, and dactylitis. Finally, for those in remission, subclinical inflammation detected by MSUS likely predicts a higher rate of flare. 

During the discussion, Bakewell reiterated that MSUS should be regarded as a tool for patient subsets who can benefit from its use, rather than being used routinely across large patient groups without a clear purpose. “It’s used to answer a question,” she said. “If you’re going to demonstrate the efficacy of a tool, you have to use it appropriately, aka when there’s a question. We don’t need to ultrasound every patient every visit.”

No external funding for the development of the guidance was noted. Ranganath has reported receiving research support from Bristol Myers Squibb and Mallinckrodt. Bakewell has reported receiving speaking/consulting fees from AbbVie, UCB, Lilly, Janssen, Novartis, Sanofi/Regeneron/Genzyme, and Pfizer. Stein had no disclosures. 

 

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

WASHINGTON — After more than a decade, the American College of Rheumatology has developed new draft guidance for the use of musculoskeletal ultrasound (MSUS) to help with diagnosis, monitoring, and prognosis of rheumatoid arthritis (RA). Though not yet finalized, the statements that came out of a first round of committee voting were unveiled at the annual meeting of the American College of Rheumatology (ACR).

The committee was charged with updating the 2012 recommendations on using MSUS in rheumatology clinical practice, explained Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program. 

More than 30,000 articles on MSUS and any arthritis have been published since 2012, and there have been significant advances and improvements in technology as well as more widespread education and use in rheumatologic clinical practice, Ranganath said. 

“There’s also been advancements in therapeutic agents and therapeutic strategies in use of these medications in rheumatoid arthritis,” Ranganath said. “We all know that the patient of today is very different than the patient of 10 years ago or 20 years ago, so this really impacts the clinical questions we ask of how we need to incorporate musculoskeletal ultrasound into our rheumatology clinical practice.” 

The process of developing the guidance involved determining key domains and then relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). Evidence came from a review of relevant literature published since 1993 in PubMed, Embase, and the Cochrane Database. A panel of 11 experts voted on the quality of the evidence as being moderate or strong for 33 statements, rejecting three that had no consensus. The committee will hold another round of voting before the guidance is published.

Erin Arnold, MD, a rheumatologist at Arnold Arthritis & Rheumatology in Skokie, Illinois, said in an interview she believes the new guidance will be “tremendously helpful,” particularly in getting “everybody on the same page” with similar practices and helping enhance diagnosis and response to therapy. 

Having used MSUS for over 20 years, Arnold said watching it evolve and seeing “this type of manuscript being put together as a resource for physicians who are taking care of inflammatory arthritis is exciting.”

“There’s not a single way we really can assess disease activity in our patients, and so having a composite of things that you’re looking at really enhances our ability to understand people’s pain,” Arnold said. 

“When you have a patient in front of you that is in so much pain but doesn’t have any active inflammation, it’s hard to want to further put them at risk with more medication,” she said. “It’s so meaningful to be able to have a conversation about ... what are other complementary interventions? How are they sleeping? How are they eating? What are they taking as far as supplements? What are they doing to decrease that kind of fear and fight-or-flight response that often can drive some of our pain?” 

 

Use of MSUS for Diagnosis Confirmation and Treatment Decisions

Gurjit S. Kaeley, MBBS, professor of medicine, division chief of rheumatology and clinical immunology, and medical director of the Musculoskeletal Ultrasound Program at the University of Florida College of Medicine, Jacksonville, reviewed the final statements for MSUS use with RA.

He said there was strong consensus that adding MSUS to clinical examination can aid diagnosis of early RA in patients with suspected RA, particularly with detection of synovitis, tenosynovitis, and erosions. There was moderate consensus that MSUS detection of tenosynovitis could predict later development of RA. 

“Furthermore, erosions do have a predictive prognostic value in telling us that these patients need more attention and more urgent attention to getting urgent care with disease-modifying medications,” Kaeley said. “Ultrasound scanning for bone erosions on a few target joints was found to be feasible in literature and provides information not available with clinical examination. Furthermore, ultrasound is more sensitive than plain radiography for the detection of erosions.” 

Moderate consensus supported a cutoff of at least 2 mm for erosions when using MSUS for diagnostic purposes. 

Strong consensus supported using MSUS of the wrist, second and third metacarpophalangeal (MCP) joints, and second and third interphalangeal (PIP) joints to aid early RA diagnosis, with moderate consensus that cutoffs of least 2 grayscale (GS) or at least 1 GS with at least 1 power Doppler (PD) at the joint level supports both an RA diagnosis and, in patients already diagnosed with RA, a positive joint.

“Grayscale-only definitions were included since equipment may not have sensitive Doppler,” Kaeley said.

Strong consensus supported scanning only a reduced set of representative or symptomatic joints to monitor disease activity with MSUS. 

 

Inflammatory Signs, Disease Progression, and Flares

There was also strong consensus for using MSUS in patients with established RA and comorbidities to help distinguish between RA-related inflammation versus inflammation from other conditions, such as gout or calcium pyrophosphate deposition disease, or versus non–RA-related pain, such as that from fibromyalgia. 

Patients with fibromyalgia, for example, “tend to have more steroid exposure and a high prevalence of biologic use because the composite disease scores tend to overestimate disease activity, especially when compared to ultrasound assessment,” Kaeley said.

Moderate consensus supported using MSUS in patients with established RA to objectively evaluate inflammation so as to eliminate age-related bias.

While MSUS signs of synovitis had only moderate consensus to be associated with radiographic progression and decline in patient-reported outcomes for patients with early RA, consensus was strong for this association in patients with established RA.

In terms of predicting disease progression with MSUS monitoring of RA disease activity, moderate consensus supported scanning the wrists and MCPs and PIPs of the hands and using the dorsal view. Kaeley emphasized that ultrasound is a clinical tool that should be used to answer a clinical question, so the sonographer or clinician needs to provide guidance on the areas to be scanned. 

Multiple standardized scoring systems exist for predicting RA disease progression, but there is no consensus on which is the most effective, and there is only moderate consensus about the validity of using dichotomous scoring with an established cutoff for a positive joint.

The combination of MSUS with clinical examination appears to be more effective at confirming RA flares than using only clinical examination, and in certain patients with established RA, MSUS may provide insights into subclinical disease activity to help maintain remission and/or potentially guide treatment decisions, “especially when coming across de-escalation therapy decisions,” Kaeley said.

Despite the negative results of treat-to-target trials that tested MSUS as a routine tool in all patients, the committee achieved strong consensus on the potential value of using MSUS in early RA to clarify clinical status and/or help achieve low disease activity or remission in certain patient populations, “such as those with patient/provider discordance or difficult physical examinations,” Kaeley said. 

 

Therapy Response, Remission, and Shared Decision-Making

Moderate consensus supported acknowledgment that using MSUS to assess response to therapy could be affected by obesity and that MSUS can distinguish active synovitis symptoms from other pain sources in difficult-to-treat RA.

In patients with established RA, the feasibility of scanning the wrists, MCPs, PIPs, and relevant symptomatic joints for remission evaluation received moderate consensus. Meanwhile, strong consensus supported the idea that increasing the number of joints scanned with MSUS could increase the certainty of the patient having achieved remission, though the guidance acknowledges that “this must be balanced against the feasibility within the context of clinical care.” 

For confirming RA remission via MSUS, strong consensus supported using GS and PD synovitis and tenosynovitis findings. But consensus was moderate for using the combination of no PD signal and minimal synovial hypertrophy to define ultrasonographic remission and for the use of MSUS detection of subclinical inflammation to predict higher flare rates for those in clinical remission.

The committee moderately agreed that MSUS can enhance patient engagement and understanding of their disease to support personalized treatment decisions, such as adjusting disease-modifying antirheumatic drug regimens.

Finally, the committee broadly agreed that “the integration of musculoskeletal ultrasound presents significant advantages in shared decision-making between healthcare providers and patients,” Kaeley said. “Ultrasound, especially with Doppler technique, provides critical insights into disease activity and structural changes not always apparent during standard examination.” 

Arnold said she particularly appreciated that the committee, rather than prescribing a specific exam, opted to be more generalizable so that people use the guidance in the context that makes the most sense for them clinically. She said it’s an incredible tool, without excluding the importance of a patient’s labs and physical examination. 

“It’s helped us make diagnoses in patients who were difficult to diagnose. It’s helped us to understand response to therapy or no response to therapy,” she said. “It makes me question all the studies that I see done on medications where they’re not looking at some type of advanced imaging.” 

No external funding was noted for the development of the guidance. Ranganath has reported receiving research support from Bristol-Myers Squibb and Mallinckrodt. Kaeley has reported receiving research funding from AbbVie, Bristol-Myers Squibb, Gilead/Galapagos, Janssen, and Novartis. Arnold had no disclosures.

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

WASHINGTON — After more than a decade, the American College of Rheumatology has developed new draft guidance for the use of musculoskeletal ultrasound (MSUS) to help with diagnosis, monitoring, and prognosis of rheumatoid arthritis (RA). Though not yet finalized, the statements that came out of a first round of committee voting were unveiled at the annual meeting of the American College of Rheumatology (ACR).

The committee was charged with updating the 2012 recommendations on using MSUS in rheumatology clinical practice, explained Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program. 

More than 30,000 articles on MSUS and any arthritis have been published since 2012, and there have been significant advances and improvements in technology as well as more widespread education and use in rheumatologic clinical practice, Ranganath said. 

“There’s also been advancements in therapeutic agents and therapeutic strategies in use of these medications in rheumatoid arthritis,” Ranganath said. “We all know that the patient of today is very different than the patient of 10 years ago or 20 years ago, so this really impacts the clinical questions we ask of how we need to incorporate musculoskeletal ultrasound into our rheumatology clinical practice.” 

The process of developing the guidance involved determining key domains and then relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). Evidence came from a review of relevant literature published since 1993 in PubMed, Embase, and the Cochrane Database. A panel of 11 experts voted on the quality of the evidence as being moderate or strong for 33 statements, rejecting three that had no consensus. The committee will hold another round of voting before the guidance is published.

Erin Arnold, MD, a rheumatologist at Arnold Arthritis & Rheumatology in Skokie, Illinois, said in an interview she believes the new guidance will be “tremendously helpful,” particularly in getting “everybody on the same page” with similar practices and helping enhance diagnosis and response to therapy. 

Having used MSUS for over 20 years, Arnold said watching it evolve and seeing “this type of manuscript being put together as a resource for physicians who are taking care of inflammatory arthritis is exciting.”

“There’s not a single way we really can assess disease activity in our patients, and so having a composite of things that you’re looking at really enhances our ability to understand people’s pain,” Arnold said. 

“When you have a patient in front of you that is in so much pain but doesn’t have any active inflammation, it’s hard to want to further put them at risk with more medication,” she said. “It’s so meaningful to be able to have a conversation about ... what are other complementary interventions? How are they sleeping? How are they eating? What are they taking as far as supplements? What are they doing to decrease that kind of fear and fight-or-flight response that often can drive some of our pain?” 

 

Use of MSUS for Diagnosis Confirmation and Treatment Decisions

Gurjit S. Kaeley, MBBS, professor of medicine, division chief of rheumatology and clinical immunology, and medical director of the Musculoskeletal Ultrasound Program at the University of Florida College of Medicine, Jacksonville, reviewed the final statements for MSUS use with RA.

He said there was strong consensus that adding MSUS to clinical examination can aid diagnosis of early RA in patients with suspected RA, particularly with detection of synovitis, tenosynovitis, and erosions. There was moderate consensus that MSUS detection of tenosynovitis could predict later development of RA. 

“Furthermore, erosions do have a predictive prognostic value in telling us that these patients need more attention and more urgent attention to getting urgent care with disease-modifying medications,” Kaeley said. “Ultrasound scanning for bone erosions on a few target joints was found to be feasible in literature and provides information not available with clinical examination. Furthermore, ultrasound is more sensitive than plain radiography for the detection of erosions.” 

Moderate consensus supported a cutoff of at least 2 mm for erosions when using MSUS for diagnostic purposes. 

Strong consensus supported using MSUS of the wrist, second and third metacarpophalangeal (MCP) joints, and second and third interphalangeal (PIP) joints to aid early RA diagnosis, with moderate consensus that cutoffs of least 2 grayscale (GS) or at least 1 GS with at least 1 power Doppler (PD) at the joint level supports both an RA diagnosis and, in patients already diagnosed with RA, a positive joint.

“Grayscale-only definitions were included since equipment may not have sensitive Doppler,” Kaeley said.

Strong consensus supported scanning only a reduced set of representative or symptomatic joints to monitor disease activity with MSUS. 

 

Inflammatory Signs, Disease Progression, and Flares

There was also strong consensus for using MSUS in patients with established RA and comorbidities to help distinguish between RA-related inflammation versus inflammation from other conditions, such as gout or calcium pyrophosphate deposition disease, or versus non–RA-related pain, such as that from fibromyalgia. 

Patients with fibromyalgia, for example, “tend to have more steroid exposure and a high prevalence of biologic use because the composite disease scores tend to overestimate disease activity, especially when compared to ultrasound assessment,” Kaeley said.

Moderate consensus supported using MSUS in patients with established RA to objectively evaluate inflammation so as to eliminate age-related bias.

While MSUS signs of synovitis had only moderate consensus to be associated with radiographic progression and decline in patient-reported outcomes for patients with early RA, consensus was strong for this association in patients with established RA.

In terms of predicting disease progression with MSUS monitoring of RA disease activity, moderate consensus supported scanning the wrists and MCPs and PIPs of the hands and using the dorsal view. Kaeley emphasized that ultrasound is a clinical tool that should be used to answer a clinical question, so the sonographer or clinician needs to provide guidance on the areas to be scanned. 

Multiple standardized scoring systems exist for predicting RA disease progression, but there is no consensus on which is the most effective, and there is only moderate consensus about the validity of using dichotomous scoring with an established cutoff for a positive joint.

The combination of MSUS with clinical examination appears to be more effective at confirming RA flares than using only clinical examination, and in certain patients with established RA, MSUS may provide insights into subclinical disease activity to help maintain remission and/or potentially guide treatment decisions, “especially when coming across de-escalation therapy decisions,” Kaeley said.

Despite the negative results of treat-to-target trials that tested MSUS as a routine tool in all patients, the committee achieved strong consensus on the potential value of using MSUS in early RA to clarify clinical status and/or help achieve low disease activity or remission in certain patient populations, “such as those with patient/provider discordance or difficult physical examinations,” Kaeley said. 

 

Therapy Response, Remission, and Shared Decision-Making

Moderate consensus supported acknowledgment that using MSUS to assess response to therapy could be affected by obesity and that MSUS can distinguish active synovitis symptoms from other pain sources in difficult-to-treat RA.

In patients with established RA, the feasibility of scanning the wrists, MCPs, PIPs, and relevant symptomatic joints for remission evaluation received moderate consensus. Meanwhile, strong consensus supported the idea that increasing the number of joints scanned with MSUS could increase the certainty of the patient having achieved remission, though the guidance acknowledges that “this must be balanced against the feasibility within the context of clinical care.” 

For confirming RA remission via MSUS, strong consensus supported using GS and PD synovitis and tenosynovitis findings. But consensus was moderate for using the combination of no PD signal and minimal synovial hypertrophy to define ultrasonographic remission and for the use of MSUS detection of subclinical inflammation to predict higher flare rates for those in clinical remission.

The committee moderately agreed that MSUS can enhance patient engagement and understanding of their disease to support personalized treatment decisions, such as adjusting disease-modifying antirheumatic drug regimens.

Finally, the committee broadly agreed that “the integration of musculoskeletal ultrasound presents significant advantages in shared decision-making between healthcare providers and patients,” Kaeley said. “Ultrasound, especially with Doppler technique, provides critical insights into disease activity and structural changes not always apparent during standard examination.” 

Arnold said she particularly appreciated that the committee, rather than prescribing a specific exam, opted to be more generalizable so that people use the guidance in the context that makes the most sense for them clinically. She said it’s an incredible tool, without excluding the importance of a patient’s labs and physical examination. 

“It’s helped us make diagnoses in patients who were difficult to diagnose. It’s helped us to understand response to therapy or no response to therapy,” she said. “It makes me question all the studies that I see done on medications where they’re not looking at some type of advanced imaging.” 

No external funding was noted for the development of the guidance. Ranganath has reported receiving research support from Bristol-Myers Squibb and Mallinckrodt. Kaeley has reported receiving research funding from AbbVie, Bristol-Myers Squibb, Gilead/Galapagos, Janssen, and Novartis. Arnold had no disclosures.

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

WASHINGTON — After more than a decade, the American College of Rheumatology has developed new draft guidance for the use of musculoskeletal ultrasound (MSUS) to help with diagnosis, monitoring, and prognosis of rheumatoid arthritis (RA). Though not yet finalized, the statements that came out of a first round of committee voting were unveiled at the annual meeting of the American College of Rheumatology (ACR).

The committee was charged with updating the 2012 recommendations on using MSUS in rheumatology clinical practice, explained Veena K. Ranganath, MD, professor of clinical medicine at the University of California, Los Angeles, and director of their Rheumatology Fellowship Musculoskeletal Ultrasound Training Program. 

More than 30,000 articles on MSUS and any arthritis have been published since 2012, and there have been significant advances and improvements in technology as well as more widespread education and use in rheumatologic clinical practice, Ranganath said. 

“There’s also been advancements in therapeutic agents and therapeutic strategies in use of these medications in rheumatoid arthritis,” Ranganath said. “We all know that the patient of today is very different than the patient of 10 years ago or 20 years ago, so this really impacts the clinical questions we ask of how we need to incorporate musculoskeletal ultrasound into our rheumatology clinical practice.” 

The process of developing the guidance involved determining key domains and then relevant clinical questions for ultrasonography using the PICO model (patient/population, intervention, comparison, and outcomes). Evidence came from a review of relevant literature published since 1993 in PubMed, Embase, and the Cochrane Database. A panel of 11 experts voted on the quality of the evidence as being moderate or strong for 33 statements, rejecting three that had no consensus. The committee will hold another round of voting before the guidance is published.

Erin Arnold, MD, a rheumatologist at Arnold Arthritis & Rheumatology in Skokie, Illinois, said in an interview she believes the new guidance will be “tremendously helpful,” particularly in getting “everybody on the same page” with similar practices and helping enhance diagnosis and response to therapy. 

Having used MSUS for over 20 years, Arnold said watching it evolve and seeing “this type of manuscript being put together as a resource for physicians who are taking care of inflammatory arthritis is exciting.”

“There’s not a single way we really can assess disease activity in our patients, and so having a composite of things that you’re looking at really enhances our ability to understand people’s pain,” Arnold said. 

“When you have a patient in front of you that is in so much pain but doesn’t have any active inflammation, it’s hard to want to further put them at risk with more medication,” she said. “It’s so meaningful to be able to have a conversation about ... what are other complementary interventions? How are they sleeping? How are they eating? What are they taking as far as supplements? What are they doing to decrease that kind of fear and fight-or-flight response that often can drive some of our pain?” 

 

Use of MSUS for Diagnosis Confirmation and Treatment Decisions

Gurjit S. Kaeley, MBBS, professor of medicine, division chief of rheumatology and clinical immunology, and medical director of the Musculoskeletal Ultrasound Program at the University of Florida College of Medicine, Jacksonville, reviewed the final statements for MSUS use with RA.

He said there was strong consensus that adding MSUS to clinical examination can aid diagnosis of early RA in patients with suspected RA, particularly with detection of synovitis, tenosynovitis, and erosions. There was moderate consensus that MSUS detection of tenosynovitis could predict later development of RA. 

“Furthermore, erosions do have a predictive prognostic value in telling us that these patients need more attention and more urgent attention to getting urgent care with disease-modifying medications,” Kaeley said. “Ultrasound scanning for bone erosions on a few target joints was found to be feasible in literature and provides information not available with clinical examination. Furthermore, ultrasound is more sensitive than plain radiography for the detection of erosions.” 

Moderate consensus supported a cutoff of at least 2 mm for erosions when using MSUS for diagnostic purposes. 

Strong consensus supported using MSUS of the wrist, second and third metacarpophalangeal (MCP) joints, and second and third interphalangeal (PIP) joints to aid early RA diagnosis, with moderate consensus that cutoffs of least 2 grayscale (GS) or at least 1 GS with at least 1 power Doppler (PD) at the joint level supports both an RA diagnosis and, in patients already diagnosed with RA, a positive joint.

“Grayscale-only definitions were included since equipment may not have sensitive Doppler,” Kaeley said.

Strong consensus supported scanning only a reduced set of representative or symptomatic joints to monitor disease activity with MSUS. 

 

Inflammatory Signs, Disease Progression, and Flares

There was also strong consensus for using MSUS in patients with established RA and comorbidities to help distinguish between RA-related inflammation versus inflammation from other conditions, such as gout or calcium pyrophosphate deposition disease, or versus non–RA-related pain, such as that from fibromyalgia. 

Patients with fibromyalgia, for example, “tend to have more steroid exposure and a high prevalence of biologic use because the composite disease scores tend to overestimate disease activity, especially when compared to ultrasound assessment,” Kaeley said.

Moderate consensus supported using MSUS in patients with established RA to objectively evaluate inflammation so as to eliminate age-related bias.

While MSUS signs of synovitis had only moderate consensus to be associated with radiographic progression and decline in patient-reported outcomes for patients with early RA, consensus was strong for this association in patients with established RA.

In terms of predicting disease progression with MSUS monitoring of RA disease activity, moderate consensus supported scanning the wrists and MCPs and PIPs of the hands and using the dorsal view. Kaeley emphasized that ultrasound is a clinical tool that should be used to answer a clinical question, so the sonographer or clinician needs to provide guidance on the areas to be scanned. 

Multiple standardized scoring systems exist for predicting RA disease progression, but there is no consensus on which is the most effective, and there is only moderate consensus about the validity of using dichotomous scoring with an established cutoff for a positive joint.

The combination of MSUS with clinical examination appears to be more effective at confirming RA flares than using only clinical examination, and in certain patients with established RA, MSUS may provide insights into subclinical disease activity to help maintain remission and/or potentially guide treatment decisions, “especially when coming across de-escalation therapy decisions,” Kaeley said.

Despite the negative results of treat-to-target trials that tested MSUS as a routine tool in all patients, the committee achieved strong consensus on the potential value of using MSUS in early RA to clarify clinical status and/or help achieve low disease activity or remission in certain patient populations, “such as those with patient/provider discordance or difficult physical examinations,” Kaeley said. 

 

Therapy Response, Remission, and Shared Decision-Making

Moderate consensus supported acknowledgment that using MSUS to assess response to therapy could be affected by obesity and that MSUS can distinguish active synovitis symptoms from other pain sources in difficult-to-treat RA.

In patients with established RA, the feasibility of scanning the wrists, MCPs, PIPs, and relevant symptomatic joints for remission evaluation received moderate consensus. Meanwhile, strong consensus supported the idea that increasing the number of joints scanned with MSUS could increase the certainty of the patient having achieved remission, though the guidance acknowledges that “this must be balanced against the feasibility within the context of clinical care.” 

For confirming RA remission via MSUS, strong consensus supported using GS and PD synovitis and tenosynovitis findings. But consensus was moderate for using the combination of no PD signal and minimal synovial hypertrophy to define ultrasonographic remission and for the use of MSUS detection of subclinical inflammation to predict higher flare rates for those in clinical remission.

The committee moderately agreed that MSUS can enhance patient engagement and understanding of their disease to support personalized treatment decisions, such as adjusting disease-modifying antirheumatic drug regimens.

Finally, the committee broadly agreed that “the integration of musculoskeletal ultrasound presents significant advantages in shared decision-making between healthcare providers and patients,” Kaeley said. “Ultrasound, especially with Doppler technique, provides critical insights into disease activity and structural changes not always apparent during standard examination.” 

Arnold said she particularly appreciated that the committee, rather than prescribing a specific exam, opted to be more generalizable so that people use the guidance in the context that makes the most sense for them clinically. She said it’s an incredible tool, without excluding the importance of a patient’s labs and physical examination. 

“It’s helped us make diagnoses in patients who were difficult to diagnose. It’s helped us to understand response to therapy or no response to therapy,” she said. “It makes me question all the studies that I see done on medications where they’re not looking at some type of advanced imaging.” 

No external funding was noted for the development of the guidance. Ranganath has reported receiving research support from Bristol-Myers Squibb and Mallinckrodt. Kaeley has reported receiving research funding from AbbVie, Bristol-Myers Squibb, Gilead/Galapagos, Janssen, and Novartis. Arnold had no disclosures.

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

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

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

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

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

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

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

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

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

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

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

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

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

The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.

What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured? 
 

The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide. 

The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.

When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)

 

Why Should Independent Practice Physicians Care About This?

Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.

It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.

Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.

 

Areas of Concern

There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.

DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%. 

There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program. 

Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.

 

Legal Challenges and Legislation

On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.

Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.

However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”

It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics. 

Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.

 

Who’s Guarding the Hen House?

The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”

HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements. 

So essentially, the fox is guarding the hen house?

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.

The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.

What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured? 
 

The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide. 

The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.

When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)

 

Why Should Independent Practice Physicians Care About This?

Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.

It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.

Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.

 

Areas of Concern

There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.

DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%. 

There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program. 

Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.

 

Legal Challenges and Legislation

On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.

Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.

However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”

It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics. 

Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.

 

Who’s Guarding the Hen House?

The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”

HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements. 

So essentially, the fox is guarding the hen house?

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.

The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.

What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured? 
 

The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide. 

The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.

When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)

 

Why Should Independent Practice Physicians Care About This?

Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.

It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.

Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.

 

Areas of Concern

There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.

DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%. 

There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program. 

Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.

 

Legal Challenges and Legislation

On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.

Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.

However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”

It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics. 

Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.

 

Who’s Guarding the Hen House?

The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”

HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements. 

So essentially, the fox is guarding the hen house?

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.