Conference Coverage

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

LISBON, PORTUGAL — The addition of a yearlong customized yoga therapy intervention to guideline-directed medical therapy (GDMT) appears to significantly improve heart failure measures associated with long-term prognosis, findings from an Indian study suggested.

The research, presented at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024 congress, involved 105 patients assigned to yoga plus GDMT or GDMT alone and demonstrated that there was a large shift in the New York Heart Association (NYHA) functional class from baseline to the 52-week follow-up.

“Yoga therapy has a beneficial impact on heart failure patients on optimal medical management,” said study presenter Ajit Singh, MD, Department of Medicine, Kasturba Medical College, Manipal, Karnataka, India, and the study “demonstrated an overall improvement in left ventricle dimensions and function.”

However, because patients were followed every day and almost a quarter had dropped out by 6 months, the study was “a challenge,” he noted. Nevertheless, the addition of yoga to GDMT could be a “game changer if we try for longer duration.”

For yoga therapy to be considered in clinical practice, a randomized study is required, said session cochair Dana Dawson, MD, PhD, professor of cardiovascular medicine and lead of the Cardiology and Cardiovascular Research Unit, University of Aberdeen, Scotland.

Patients in the current analysis, however, were not randomly allocated to treatment group, which resulted in baseline discrepancies that made the groups “incomparable,” Dr. Dawson explained.

Still, the study showed that yoga is feasible in this patient group and that, even just comparing baseline and follow-up outcomes in the yoga group, there were some significant results.

“It is effective in implementing a change,” she said, “and whether that change is clinically effective needs to be tested in a clinic in a randomized study.”
 

Why Yoga May Be Particularly Effective

Yoga may be different from other exercise and lifestyle interventions because it is “also about meditation and meeting with your own self,” which corresponds to a form of cognitive behavioral therapy, albeit “conducted in singular manner,” she added.

“It’s not going to be everyone’s cup of tea, and not everyone is going to be inclined to do it,” but it could be suitable in countries where yoga is more commonly practiced as a behavioral, as opposed to lifestyle, intervention, said Dr. Dawson.

Heart failure is a “complex chronic disease” that is a “prime cause of concern for healthcare sectors worldwide,” not least in India, where there is a “very high prevalence” of the disease, Dr. Singh noted.

Evidence from the literature indicates that yoga and other lifestyle modifications can improve the quality of life of patients with heart failure, alongside measures such as left ventricular ejection fraction (LVEF) and NYHA functional class, he said. However, the researchers did not find any study that looked at yoga therapy as an adjunct to standard-of-care treatment.
 

How Yoga Was Applied

They recruited patients aged 30-70 years with persistent heart failure symptoms, an LVEF of < 45%, and NYHA class III or lower heart failure. All participants had undergone a cardiac procedure 6-12 months previously, and all were receiving optimal GDMT.

Patients were assigned in a nonrandomized fashion to GDMT with or without a customized yoga program. Eight forms of pranayama breath work, meditation, and relaxation techniques were taught to patients in the yoga group by experienced hospital faculty.

They were supervised for 1 week and then advised to continue self-administered yoga at home once a week for 45 minutes. After each home session, an instructor followed up with each study participant to monitor progress.

All participants were assessed with echocardiography and other measures, including physical activities, to determine NYHA functional status at baseline, 6 months, and 1 year.

Of the 110 patients recruited, 25 had dropped out by 6 months. Of the remaining 85 patients included in the analysis, 40 were assigned to the yoga group. The average age was 49 years, and 70 (82%) of the participants were men. The lack of women in the study is a “major drawback,” Dr. Singh noted.

Women did not want to participate, he explained, “because they were afraid to get the follow-up,” saying, “We will not be able to follow this yoga therapy for 1 year.”

After 52 weeks, patients in the yoga group had significantly greater reductions from baseline in systolic and diastolic blood pressure, heart rate, and body mass index than those in the GDMT-alone group (P < .05 for all).

Patients in the yoga group also experienced significantly greater improvements in ejection fraction, increasing from an average of 41.5% to 44.4% over the course of the study. In contrast, ejection fraction decreased from 42.3% to 41.6% in the GDMT-alone group (P < .05).

Crucially, there was a marked improvement in the NYHA class in the yoga group.

With yoga, the proportion of patients with class I heart failure increased from 12% to 47% over the 52 weeks of the study, whereas the proportion with class II heart failure decreased from 57% to 30%, and the proportion with class III heart failure decreased from 30% to 12% (P <  .001). In both the yoga and GDMT-alone groups, the proportion of patients with class IV disease increased from 0% to about 10%.

No funding was declared. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

LISBON, PORTUGAL — The addition of a yearlong customized yoga therapy intervention to guideline-directed medical therapy (GDMT) appears to significantly improve heart failure measures associated with long-term prognosis, findings from an Indian study suggested.

The research, presented at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024 congress, involved 105 patients assigned to yoga plus GDMT or GDMT alone and demonstrated that there was a large shift in the New York Heart Association (NYHA) functional class from baseline to the 52-week follow-up.

“Yoga therapy has a beneficial impact on heart failure patients on optimal medical management,” said study presenter Ajit Singh, MD, Department of Medicine, Kasturba Medical College, Manipal, Karnataka, India, and the study “demonstrated an overall improvement in left ventricle dimensions and function.”

However, because patients were followed every day and almost a quarter had dropped out by 6 months, the study was “a challenge,” he noted. Nevertheless, the addition of yoga to GDMT could be a “game changer if we try for longer duration.”

For yoga therapy to be considered in clinical practice, a randomized study is required, said session cochair Dana Dawson, MD, PhD, professor of cardiovascular medicine and lead of the Cardiology and Cardiovascular Research Unit, University of Aberdeen, Scotland.

Patients in the current analysis, however, were not randomly allocated to treatment group, which resulted in baseline discrepancies that made the groups “incomparable,” Dr. Dawson explained.

Still, the study showed that yoga is feasible in this patient group and that, even just comparing baseline and follow-up outcomes in the yoga group, there were some significant results.

“It is effective in implementing a change,” she said, “and whether that change is clinically effective needs to be tested in a clinic in a randomized study.”
 

Why Yoga May Be Particularly Effective

Yoga may be different from other exercise and lifestyle interventions because it is “also about meditation and meeting with your own self,” which corresponds to a form of cognitive behavioral therapy, albeit “conducted in singular manner,” she added.

“It’s not going to be everyone’s cup of tea, and not everyone is going to be inclined to do it,” but it could be suitable in countries where yoga is more commonly practiced as a behavioral, as opposed to lifestyle, intervention, said Dr. Dawson.

Heart failure is a “complex chronic disease” that is a “prime cause of concern for healthcare sectors worldwide,” not least in India, where there is a “very high prevalence” of the disease, Dr. Singh noted.

Evidence from the literature indicates that yoga and other lifestyle modifications can improve the quality of life of patients with heart failure, alongside measures such as left ventricular ejection fraction (LVEF) and NYHA functional class, he said. However, the researchers did not find any study that looked at yoga therapy as an adjunct to standard-of-care treatment.
 

How Yoga Was Applied

They recruited patients aged 30-70 years with persistent heart failure symptoms, an LVEF of < 45%, and NYHA class III or lower heart failure. All participants had undergone a cardiac procedure 6-12 months previously, and all were receiving optimal GDMT.

Patients were assigned in a nonrandomized fashion to GDMT with or without a customized yoga program. Eight forms of pranayama breath work, meditation, and relaxation techniques were taught to patients in the yoga group by experienced hospital faculty.

They were supervised for 1 week and then advised to continue self-administered yoga at home once a week for 45 minutes. After each home session, an instructor followed up with each study participant to monitor progress.

All participants were assessed with echocardiography and other measures, including physical activities, to determine NYHA functional status at baseline, 6 months, and 1 year.

Of the 110 patients recruited, 25 had dropped out by 6 months. Of the remaining 85 patients included in the analysis, 40 were assigned to the yoga group. The average age was 49 years, and 70 (82%) of the participants were men. The lack of women in the study is a “major drawback,” Dr. Singh noted.

Women did not want to participate, he explained, “because they were afraid to get the follow-up,” saying, “We will not be able to follow this yoga therapy for 1 year.”

After 52 weeks, patients in the yoga group had significantly greater reductions from baseline in systolic and diastolic blood pressure, heart rate, and body mass index than those in the GDMT-alone group (P < .05 for all).

Patients in the yoga group also experienced significantly greater improvements in ejection fraction, increasing from an average of 41.5% to 44.4% over the course of the study. In contrast, ejection fraction decreased from 42.3% to 41.6% in the GDMT-alone group (P < .05).

Crucially, there was a marked improvement in the NYHA class in the yoga group.

With yoga, the proportion of patients with class I heart failure increased from 12% to 47% over the 52 weeks of the study, whereas the proportion with class II heart failure decreased from 57% to 30%, and the proportion with class III heart failure decreased from 30% to 12% (P <  .001). In both the yoga and GDMT-alone groups, the proportion of patients with class IV disease increased from 0% to about 10%.

No funding was declared. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

LISBON, PORTUGAL — The addition of a yearlong customized yoga therapy intervention to guideline-directed medical therapy (GDMT) appears to significantly improve heart failure measures associated with long-term prognosis, findings from an Indian study suggested.

The research, presented at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024 congress, involved 105 patients assigned to yoga plus GDMT or GDMT alone and demonstrated that there was a large shift in the New York Heart Association (NYHA) functional class from baseline to the 52-week follow-up.

“Yoga therapy has a beneficial impact on heart failure patients on optimal medical management,” said study presenter Ajit Singh, MD, Department of Medicine, Kasturba Medical College, Manipal, Karnataka, India, and the study “demonstrated an overall improvement in left ventricle dimensions and function.”

However, because patients were followed every day and almost a quarter had dropped out by 6 months, the study was “a challenge,” he noted. Nevertheless, the addition of yoga to GDMT could be a “game changer if we try for longer duration.”

For yoga therapy to be considered in clinical practice, a randomized study is required, said session cochair Dana Dawson, MD, PhD, professor of cardiovascular medicine and lead of the Cardiology and Cardiovascular Research Unit, University of Aberdeen, Scotland.

Patients in the current analysis, however, were not randomly allocated to treatment group, which resulted in baseline discrepancies that made the groups “incomparable,” Dr. Dawson explained.

Still, the study showed that yoga is feasible in this patient group and that, even just comparing baseline and follow-up outcomes in the yoga group, there were some significant results.

“It is effective in implementing a change,” she said, “and whether that change is clinically effective needs to be tested in a clinic in a randomized study.”
 

Why Yoga May Be Particularly Effective

Yoga may be different from other exercise and lifestyle interventions because it is “also about meditation and meeting with your own self,” which corresponds to a form of cognitive behavioral therapy, albeit “conducted in singular manner,” she added.

“It’s not going to be everyone’s cup of tea, and not everyone is going to be inclined to do it,” but it could be suitable in countries where yoga is more commonly practiced as a behavioral, as opposed to lifestyle, intervention, said Dr. Dawson.

Heart failure is a “complex chronic disease” that is a “prime cause of concern for healthcare sectors worldwide,” not least in India, where there is a “very high prevalence” of the disease, Dr. Singh noted.

Evidence from the literature indicates that yoga and other lifestyle modifications can improve the quality of life of patients with heart failure, alongside measures such as left ventricular ejection fraction (LVEF) and NYHA functional class, he said. However, the researchers did not find any study that looked at yoga therapy as an adjunct to standard-of-care treatment.
 

How Yoga Was Applied

They recruited patients aged 30-70 years with persistent heart failure symptoms, an LVEF of < 45%, and NYHA class III or lower heart failure. All participants had undergone a cardiac procedure 6-12 months previously, and all were receiving optimal GDMT.

Patients were assigned in a nonrandomized fashion to GDMT with or without a customized yoga program. Eight forms of pranayama breath work, meditation, and relaxation techniques were taught to patients in the yoga group by experienced hospital faculty.

They were supervised for 1 week and then advised to continue self-administered yoga at home once a week for 45 minutes. After each home session, an instructor followed up with each study participant to monitor progress.

All participants were assessed with echocardiography and other measures, including physical activities, to determine NYHA functional status at baseline, 6 months, and 1 year.

Of the 110 patients recruited, 25 had dropped out by 6 months. Of the remaining 85 patients included in the analysis, 40 were assigned to the yoga group. The average age was 49 years, and 70 (82%) of the participants were men. The lack of women in the study is a “major drawback,” Dr. Singh noted.

Women did not want to participate, he explained, “because they were afraid to get the follow-up,” saying, “We will not be able to follow this yoga therapy for 1 year.”

After 52 weeks, patients in the yoga group had significantly greater reductions from baseline in systolic and diastolic blood pressure, heart rate, and body mass index than those in the GDMT-alone group (P < .05 for all).

Patients in the yoga group also experienced significantly greater improvements in ejection fraction, increasing from an average of 41.5% to 44.4% over the course of the study. In contrast, ejection fraction decreased from 42.3% to 41.6% in the GDMT-alone group (P < .05).

Crucially, there was a marked improvement in the NYHA class in the yoga group.

With yoga, the proportion of patients with class I heart failure increased from 12% to 47% over the 52 weeks of the study, whereas the proportion with class II heart failure decreased from 57% to 30%, and the proportion with class III heart failure decreased from 30% to 12% (P <  .001). In both the yoga and GDMT-alone groups, the proportion of patients with class IV disease increased from 0% to about 10%.

No funding was declared. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

Despite an expanding arsenal of disease-modifying antirheumatic drugs (DMARDs), many patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) still struggle to reach remission even after trying multiple advanced treatments.

Now, international groups of experts are working to better define these “difficult-to-treat” patients to both inform care and improve selection of participants for future clinical trials.

“The idea is rather simple, and the need is relatively ubiquitous,” Denis Poddubnyy, MD, of the Charité – Universitätsmedizin Berlin and the German Rheumatism Research Center Berlin, both in Berlin, Germany, said in an interview. He is the co-primary investigator for the ongoing Assessment of SpondyloArthritis International Society (ASAS) project to develop a consensus definition of difficult-to-treat axSpA.

According to ASAS, only 40%-50% of patients with axSpA achieve a 40% improvement in ASAS response criteria (ASAS40), and few (10%-20%) achieve remission in the first 4-6 months of treatment.

Multiple Reasons for Nonresponse

“While the term difficult-to-treat can refer to refractory disease, that is not the only reason why a patient might not be responding to medication. In fact, it’s likely that truly biologically refractory disease makes up only a fraction of cases that respond inadequately to treatment,” said Shikha Singla, MD, who directs the psoriatic arthritis program at the Medical College of Wisconsin in Milwaukee. She is also involved with the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) initiative to define Difficult-to-Treat and Complex-to-Manage PsA.

Medical College of Wisconsin

“Apart from the persistent articular and periarticular inflammation, there could be multiple noninflammatory factors that may be contributing to this treatment-resistant disease, including comorbid conditions such as obesity, cardiovascular disease, fibromyalgia, and even social factors such as limited access to medications,” she told this news organization. “Given these complexities, it is a matter of supreme importance to recognize and carefully delineate the elements that contribute to treatment refractory disease: Is it truly the inflammation, or are there noninflammatory components that are causing the treatment failure, or a combination of the two?”

Other contributing factors could be depression, hypersensitization, and comorbidities that prevent certain treatment approaches, added Fabian Proft, MD, also of Charité – Universitätsmedizin Berlin. Dr. Proft discussed these difficult-to-treat definition efforts at the recent Spondyloarthritis Research and Treatment Network (SPARTAN) annual meeting held in Cleveland. Patients also might not be taking their medication regularly and may be seeking alternative medicine approaches, he said.

Dr. Proft

The Definitions

Terminology for these two groups can vary by professional society. The European Alliance of Associations for Rheumatology (EULAR) published a definition for “difficult-to-treat” rheumatoid arthritis (RA) that includes cases with “both inflammatory activity and/or noninflammatory complaints.”

The definition includes three criteria:

1) Treatment according to EULAR recommendation and failure of at least two biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated)

2) Signs suggestive of active/progressive disease, including at least one of the following:

• Moderate disease activity (according to validated composite measures including joint counts)
• Signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease, whether joint-related or other
• Inability to taper glucocorticoid treatment
• Rapid radiographic progression (with or without signs of active disease)
• RA symptoms that are causing a reduction in quality of life

3) Symptom/sign management perceived as problematic by the rheumatologist or the patient

All three criteria must be met.

Both GRAPPA and ASAS plan to use the term “difficult-to-treat” or “treatment refractory” to describe true biologically refractory inflammatory disease and are categorizing the larger, heterogeneous group of nonresponders as “difficult-to-manage” (ASAS) or “complex-to-manage” (GRAPPA).

According to Dr. Poddubnyy, the agreed ASAS definition of difficult-to-manage has several similarities with EULAR’s RA definition, including three pillars:

• Treatment according to existing recommendations and failure of at least two different bDMARDs or tsDMARDs with different mechanisms
• Having signs and symptoms of disease (measured by high disease activity by certain disease activity indexes, persistently elevated C-reactive protein, inflammation on MRI, or rapid radiographic spinal progression)
• Symptoms/signs of disease that are considered problematic by the provider or patient

The definition was approved in January, and the manuscript is in the works, Dr. Poddubnyy said.

The GRAPPA project on PsA is still in its early stages, which so far has included a comprehensive literature review as well as a survey of GRAPPA members across 47 countries. The group is generally in agreement that two separate definitions for nonresponse to treatment are necessary, and that the “difficult-to-treat” definition — which identifies true refractory disease — should include objective signs of inflammation, Dr. Singla said.
 

Looking Forward

The next step of the ASAS project is to “define the pathway” from difficult-to-manage axSpA to treatment refractory disease, Dr. Poddubnyy said.

“What should be ruled out in order to exclude so-called noninflammatory causes of pain?” he continued. “It will require some Delphi exercises and [a] consensus approach.”

Proft anticipates that this treatment refractory definition in both axSpA and PsA will be most useful in research, rather than clinical practice.

“It is really important to have unified definition criteria to shape as homogeneous a cohort as possible,” he said, for future clinical trials in this population.

On the other hand, the complex/difficult-to-manage definition may be more useful for clinical practice, Dr. Proft thought.

“If you see a patient not responding to treatment, the easiest thing you can do would be to change treatment,” like swapping one biologic for another, Dr. Poddubnyy added, “but this would not be the right approach in every patient.” One goal of these initiatives is to give guidance on “what things should be looked after or excluded before you conclude this is biological [nonresponse],” he said.

Dr. Singla consults for AbbVie, Janssen, and UCB and received research funding from Eli Lilly. Dr. Poddubnyy disclosed serving as a speaker, consultant, and/or research grant recipient for multiple companies including AbbVie, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, GlaxoSmithKline, Novartis, and UCB. Dr. Proft reported receiving research grants, consultant fees, or support for attending meetings and/or travel from Amgen, AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, UCB, Medscape Medical News, Galapagos, and Hexal. Dr. Proft also participants on a data safety monitoring board or advisory board for AbbVie, Celgene, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

Despite an expanding arsenal of disease-modifying antirheumatic drugs (DMARDs), many patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) still struggle to reach remission even after trying multiple advanced treatments.

Now, international groups of experts are working to better define these “difficult-to-treat” patients to both inform care and improve selection of participants for future clinical trials.

“The idea is rather simple, and the need is relatively ubiquitous,” Denis Poddubnyy, MD, of the Charité – Universitätsmedizin Berlin and the German Rheumatism Research Center Berlin, both in Berlin, Germany, said in an interview. He is the co-primary investigator for the ongoing Assessment of SpondyloArthritis International Society (ASAS) project to develop a consensus definition of difficult-to-treat axSpA.

According to ASAS, only 40%-50% of patients with axSpA achieve a 40% improvement in ASAS response criteria (ASAS40), and few (10%-20%) achieve remission in the first 4-6 months of treatment.

Multiple Reasons for Nonresponse

“While the term difficult-to-treat can refer to refractory disease, that is not the only reason why a patient might not be responding to medication. In fact, it’s likely that truly biologically refractory disease makes up only a fraction of cases that respond inadequately to treatment,” said Shikha Singla, MD, who directs the psoriatic arthritis program at the Medical College of Wisconsin in Milwaukee. She is also involved with the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) initiative to define Difficult-to-Treat and Complex-to-Manage PsA.

Medical College of Wisconsin

“Apart from the persistent articular and periarticular inflammation, there could be multiple noninflammatory factors that may be contributing to this treatment-resistant disease, including comorbid conditions such as obesity, cardiovascular disease, fibromyalgia, and even social factors such as limited access to medications,” she told this news organization. “Given these complexities, it is a matter of supreme importance to recognize and carefully delineate the elements that contribute to treatment refractory disease: Is it truly the inflammation, or are there noninflammatory components that are causing the treatment failure, or a combination of the two?”

Other contributing factors could be depression, hypersensitization, and comorbidities that prevent certain treatment approaches, added Fabian Proft, MD, also of Charité – Universitätsmedizin Berlin. Dr. Proft discussed these difficult-to-treat definition efforts at the recent Spondyloarthritis Research and Treatment Network (SPARTAN) annual meeting held in Cleveland. Patients also might not be taking their medication regularly and may be seeking alternative medicine approaches, he said.

Dr. Proft

The Definitions

Terminology for these two groups can vary by professional society. The European Alliance of Associations for Rheumatology (EULAR) published a definition for “difficult-to-treat” rheumatoid arthritis (RA) that includes cases with “both inflammatory activity and/or noninflammatory complaints.”

The definition includes three criteria:

1) Treatment according to EULAR recommendation and failure of at least two biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated)

2) Signs suggestive of active/progressive disease, including at least one of the following:

• Moderate disease activity (according to validated composite measures including joint counts)
• Signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease, whether joint-related or other
• Inability to taper glucocorticoid treatment
• Rapid radiographic progression (with or without signs of active disease)
• RA symptoms that are causing a reduction in quality of life

3) Symptom/sign management perceived as problematic by the rheumatologist or the patient

All three criteria must be met.

Both GRAPPA and ASAS plan to use the term “difficult-to-treat” or “treatment refractory” to describe true biologically refractory inflammatory disease and are categorizing the larger, heterogeneous group of nonresponders as “difficult-to-manage” (ASAS) or “complex-to-manage” (GRAPPA).

According to Dr. Poddubnyy, the agreed ASAS definition of difficult-to-manage has several similarities with EULAR’s RA definition, including three pillars:

• Treatment according to existing recommendations and failure of at least two different bDMARDs or tsDMARDs with different mechanisms
• Having signs and symptoms of disease (measured by high disease activity by certain disease activity indexes, persistently elevated C-reactive protein, inflammation on MRI, or rapid radiographic spinal progression)
• Symptoms/signs of disease that are considered problematic by the provider or patient

The definition was approved in January, and the manuscript is in the works, Dr. Poddubnyy said.

The GRAPPA project on PsA is still in its early stages, which so far has included a comprehensive literature review as well as a survey of GRAPPA members across 47 countries. The group is generally in agreement that two separate definitions for nonresponse to treatment are necessary, and that the “difficult-to-treat” definition — which identifies true refractory disease — should include objective signs of inflammation, Dr. Singla said.
 

Looking Forward

The next step of the ASAS project is to “define the pathway” from difficult-to-manage axSpA to treatment refractory disease, Dr. Poddubnyy said.

“What should be ruled out in order to exclude so-called noninflammatory causes of pain?” he continued. “It will require some Delphi exercises and [a] consensus approach.”

Proft anticipates that this treatment refractory definition in both axSpA and PsA will be most useful in research, rather than clinical practice.

“It is really important to have unified definition criteria to shape as homogeneous a cohort as possible,” he said, for future clinical trials in this population.

On the other hand, the complex/difficult-to-manage definition may be more useful for clinical practice, Dr. Proft thought.

“If you see a patient not responding to treatment, the easiest thing you can do would be to change treatment,” like swapping one biologic for another, Dr. Poddubnyy added, “but this would not be the right approach in every patient.” One goal of these initiatives is to give guidance on “what things should be looked after or excluded before you conclude this is biological [nonresponse],” he said.

Dr. Singla consults for AbbVie, Janssen, and UCB and received research funding from Eli Lilly. Dr. Poddubnyy disclosed serving as a speaker, consultant, and/or research grant recipient for multiple companies including AbbVie, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, GlaxoSmithKline, Novartis, and UCB. Dr. Proft reported receiving research grants, consultant fees, or support for attending meetings and/or travel from Amgen, AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, UCB, Medscape Medical News, Galapagos, and Hexal. Dr. Proft also participants on a data safety monitoring board or advisory board for AbbVie, Celgene, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

Despite an expanding arsenal of disease-modifying antirheumatic drugs (DMARDs), many patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) still struggle to reach remission even after trying multiple advanced treatments.

Now, international groups of experts are working to better define these “difficult-to-treat” patients to both inform care and improve selection of participants for future clinical trials.

“The idea is rather simple, and the need is relatively ubiquitous,” Denis Poddubnyy, MD, of the Charité – Universitätsmedizin Berlin and the German Rheumatism Research Center Berlin, both in Berlin, Germany, said in an interview. He is the co-primary investigator for the ongoing Assessment of SpondyloArthritis International Society (ASAS) project to develop a consensus definition of difficult-to-treat axSpA.

According to ASAS, only 40%-50% of patients with axSpA achieve a 40% improvement in ASAS response criteria (ASAS40), and few (10%-20%) achieve remission in the first 4-6 months of treatment.

Multiple Reasons for Nonresponse

“While the term difficult-to-treat can refer to refractory disease, that is not the only reason why a patient might not be responding to medication. In fact, it’s likely that truly biologically refractory disease makes up only a fraction of cases that respond inadequately to treatment,” said Shikha Singla, MD, who directs the psoriatic arthritis program at the Medical College of Wisconsin in Milwaukee. She is also involved with the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) initiative to define Difficult-to-Treat and Complex-to-Manage PsA.

Medical College of Wisconsin

“Apart from the persistent articular and periarticular inflammation, there could be multiple noninflammatory factors that may be contributing to this treatment-resistant disease, including comorbid conditions such as obesity, cardiovascular disease, fibromyalgia, and even social factors such as limited access to medications,” she told this news organization. “Given these complexities, it is a matter of supreme importance to recognize and carefully delineate the elements that contribute to treatment refractory disease: Is it truly the inflammation, or are there noninflammatory components that are causing the treatment failure, or a combination of the two?”

Other contributing factors could be depression, hypersensitization, and comorbidities that prevent certain treatment approaches, added Fabian Proft, MD, also of Charité – Universitätsmedizin Berlin. Dr. Proft discussed these difficult-to-treat definition efforts at the recent Spondyloarthritis Research and Treatment Network (SPARTAN) annual meeting held in Cleveland. Patients also might not be taking their medication regularly and may be seeking alternative medicine approaches, he said.

Dr. Proft

The Definitions

Terminology for these two groups can vary by professional society. The European Alliance of Associations for Rheumatology (EULAR) published a definition for “difficult-to-treat” rheumatoid arthritis (RA) that includes cases with “both inflammatory activity and/or noninflammatory complaints.”

The definition includes three criteria:

1) Treatment according to EULAR recommendation and failure of at least two biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated)

2) Signs suggestive of active/progressive disease, including at least one of the following:

• Moderate disease activity (according to validated composite measures including joint counts)
• Signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease, whether joint-related or other
• Inability to taper glucocorticoid treatment
• Rapid radiographic progression (with or without signs of active disease)
• RA symptoms that are causing a reduction in quality of life

3) Symptom/sign management perceived as problematic by the rheumatologist or the patient

All three criteria must be met.

Both GRAPPA and ASAS plan to use the term “difficult-to-treat” or “treatment refractory” to describe true biologically refractory inflammatory disease and are categorizing the larger, heterogeneous group of nonresponders as “difficult-to-manage” (ASAS) or “complex-to-manage” (GRAPPA).

According to Dr. Poddubnyy, the agreed ASAS definition of difficult-to-manage has several similarities with EULAR’s RA definition, including three pillars:

• Treatment according to existing recommendations and failure of at least two different bDMARDs or tsDMARDs with different mechanisms
• Having signs and symptoms of disease (measured by high disease activity by certain disease activity indexes, persistently elevated C-reactive protein, inflammation on MRI, or rapid radiographic spinal progression)
• Symptoms/signs of disease that are considered problematic by the provider or patient

The definition was approved in January, and the manuscript is in the works, Dr. Poddubnyy said.

The GRAPPA project on PsA is still in its early stages, which so far has included a comprehensive literature review as well as a survey of GRAPPA members across 47 countries. The group is generally in agreement that two separate definitions for nonresponse to treatment are necessary, and that the “difficult-to-treat” definition — which identifies true refractory disease — should include objective signs of inflammation, Dr. Singla said.
 

Looking Forward

The next step of the ASAS project is to “define the pathway” from difficult-to-manage axSpA to treatment refractory disease, Dr. Poddubnyy said.

“What should be ruled out in order to exclude so-called noninflammatory causes of pain?” he continued. “It will require some Delphi exercises and [a] consensus approach.”

Proft anticipates that this treatment refractory definition in both axSpA and PsA will be most useful in research, rather than clinical practice.

“It is really important to have unified definition criteria to shape as homogeneous a cohort as possible,” he said, for future clinical trials in this population.

On the other hand, the complex/difficult-to-manage definition may be more useful for clinical practice, Dr. Proft thought.

“If you see a patient not responding to treatment, the easiest thing you can do would be to change treatment,” like swapping one biologic for another, Dr. Poddubnyy added, “but this would not be the right approach in every patient.” One goal of these initiatives is to give guidance on “what things should be looked after or excluded before you conclude this is biological [nonresponse],” he said.

Dr. Singla consults for AbbVie, Janssen, and UCB and received research funding from Eli Lilly. Dr. Poddubnyy disclosed serving as a speaker, consultant, and/or research grant recipient for multiple companies including AbbVie, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, GlaxoSmithKline, Novartis, and UCB. Dr. Proft reported receiving research grants, consultant fees, or support for attending meetings and/or travel from Amgen, AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, UCB, Medscape Medical News, Galapagos, and Hexal. Dr. Proft also participants on a data safety monitoring board or advisory board for AbbVie, Celgene, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.

The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.

At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.

“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”

Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”

Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”

Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
 

Risk-Stratifying With SSc-Nonspecific Antibodies

Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”

A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
 

High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc

At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).

“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.

In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.

Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.

“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”

After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.

The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”

Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.

Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.

The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.

At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.

“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”

Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”

Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”

Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
 

Risk-Stratifying With SSc-Nonspecific Antibodies

Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”

A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
 

High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc

At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).

“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.

In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.

Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.

“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”

After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.

The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”

Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.

Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

VIENNA — Anti-Ro/SSA antibodies may help predict which patients with systemic sclerosis (SSc) are at a greater risk for interstitial lung disease (ILD) and may serve as a biomarker to guide screening, according to an analysis of data from a large European cohort.

The researchers were led by Blaž Burja, MD, PhD, a physician-scientist at the Center of Experimental Rheumatology, University Hospital Zürich, Switzerland, who reported that anti-Ro/SSA antibodies are a risk factor for ILD, with an odds ratio of 1.24, in patients with SSc.

At the annual European Congress of Rheumatology, he presented the findings of the study that aimed to find out if SSc-nonspecific antibodies might help better risk-stratify patients with SSc, focusing on lung involvement. “Among them, anti-Ro/SSA antibodies have been shown to be associated with interstitial lung disease in different connective tissue diseases,” Dr. Burja pointed out.

“A total of 15% of all patients in the SSc cohort presented with anti-Ro/SSA antibodies, and this subgroup presented with distinct clinical features: Importantly, higher prevalence of ILD and lower DLCO% [diffusing capacity of the lungs for carbon monoxide] in patients with established ILD,” reported Dr. Burja. “However, these anti-Ro/SSA antibodies do not predict ILD progression, death, or overall disease progression.”

Based on the findings, Dr. Burja suggested that these antibodies be incorporated into routine clinical practice to identify patients with SSc who have a high risk for ILD. He noted that “this has specific importance in clinical settings without availability of high-resolution computed tomography (HRCT), where anti-Ro/SSA antibodies could represent an additional biomarker to guide the screening process, in particular, in patients without SSc-specific antibodies.”

Caroline Ospelt, MD, PhD, co-moderator of the session and scientific program chair of EULAR 2024, told this news organization that the study was unique in its approach to studying ILD risk by “looking outside the box, so not just at specific antibodies but whether cross-disease antibodies may have value in stratifying patients and help predict risk of lung involvement and possibly monitor these patients.”

Dr. Ospelt, professor of experimental rheumatology at University Hospital Zürich, who was not involved in the study, noted: “It might also be the case that we could adapt this concept and use these antibodies in other rheumatic diseases, too, not just systemic sclerosis, to predict lung involvement.”
 

Risk-Stratifying With SSc-Nonspecific Antibodies

Dr. Burja explained that despite better stratification of patients with SSc with SSc-specific antibodies, “in clinical practice, we see large heterogeneity, and individual prognosis with regards to outcomes is still unpredictable, so we wanted to know whether by using nonspecific autoantibodies we might be better able to risk-stratify these patients.”

A study population of 4421 with at least one follow-up visit, including 3060 patients with available follow-up serologic data, was drawn from the European Scleroderma Trials and Research group database (n = 22,482). Of these 3060 patients, 461 were positive for anti-Ro/SSA antibodies and 2599 were negative. The researchers analyzed the relationships between baseline characteristics and the development or progression of ILD over 2.7 years of follow-up. Incident, de novo ILD was defined based on its presence on HRCT, and progression was defined by whether the percentage of predicted forced vital capacity (FVC%) dropped ≥ 10%, FVC% dropped 5%-9% in association with a DLCO% drop ≥ 15%, or FVC% dropped > 5%. Deaths from all causes and prognostic factors for the progression of lung fibrosis during follow-up were recorded.
 

High Prevalence of ILD With Anti-Ro/SSA Antibodies in SSc

At baseline, patients with anti-Ro/SSA antibodies were aged 55-56 years, 84%-87% were women, and muscular involvement was present in 18% of patients positive for anti-Ro/SSA antibodies and 12.5% of those who were negative (P < .001). According to HRCT, ILD was present in 56.2% of patients positive for anti-Ro/SSA antibodies and in 47.8% of those who were negative (P = .001). FVC% was 92.5% in patients positive for anti-Ro/SSA antibodies and 95.7% in those who were negative (P = .002). DLCO% was 66.9% in patients positive for anti-Ro/SSA antibodies and 71% in those who were negative (P < .001).

“A total of 15% of all SSc patients presented as positive for anti-Ro/SSA antibodies, and these patients all presented with higher prevalence of SSA-nonspecific antibodies, too: Of note, those with anti-La/SSB and anti-U1/RNP and rheumatoid factor,” Dr. Burja reported.

In patients with anti-U1/RNP autoantibodies, 1% were positive and 4% were negative for anti-Ro/SSA antibodies; in those with anti-La/SSB autoantibodies, 17% were positive and 1% were negative for anti-Ro/SSA antibodies; and in those with rheumatoid factor, 28% were positive and 14% were negative for anti-Ro/SSA antibodies.

Dr. Burja pointed out that the average disease duration in the study cohort at baseline was 7 years, “and at this timepoint, we expect to see some common disease manifestations. Specifically, higher muscular involvement and higher ILD based on HRCT.

“We decided to focus on patients with established ILD at baseline,” said Dr. Burja. “Anti-Ro/SSA-positive patients with established ILD at baseline presented with lower DLCO values at 59% in patients positive for anti-Ro/SSA antibodies and 61% for those who were negative.”

After conducting a multivariable analysis of 14,066 healthcare visits and adjusting for known risk factors for ILD, the researchers concluded that anti-Ro/SSA antibodies are an independent risk factor for ILD, with an odds ratio of 1.24 (95% CI, 1.07-1.44; P = .006). They also determined that anti-Ro/SSA antibodies are a risk factor for lower DLCO values in patients with ILD, with a regression coefficient of −1.93.

The researchers then explored the progression of ILD and overall disease progression and survival during the follow-up period in a longitudinal analysis. “However, anti-Ro/SSA antibodies were not found to predict the progression of ILD,” reported Dr. Burja, adding that this was true regardless of the definition of ILD progression used. “Nor did anti-Ro/SSA antibodies do not predict survival or overall disease progression.”

Dr. Burja pointed out the limitations in his study, including the lack of standardized criteria for all centers to assess anti-Ro/SSA positivity; there was a lack of discrimination between anti-Ro52 and anti-Ro60 subtypes, and there were no standardized applicable criteria to study lung progression in SSc.

Dr. Burja and Dr. Ospelt had no relevant financial disclosures.
 

A version of this article appeared on Medscape.com.

VIENNA — In patients with rheumatoid arthritis (RA), Janus kinase inhibitors (JAKi) are associated with a substantially greater risk for herpes zoster, but the risk for other types of infections is about the same and often numerically lower relative to biologic disease-modifying antirheumatic drugs (bDMARDs), according to new data from the JAK-pot study.

“In the real world, we found no significantly greater risk of serious or nonserious infections, with the exception of herpes zoster,” said Romain Aymon, a statistician in the Department of Rheumatology at the University Hospital of Geneva, Switzerland.

Ted Bosworth/Medscape Medical News

This finding is the latest analysis generated by JAK-pot, a collaboration of 20 national registries to answer real-world questions about the efficacy and safety of JAKi in rheumatic diseases. These data have already been used to address such issues as relative rates of discontinuation for JAKi vs bDMARDs and to compare outcomes of RA patients who are switched to a bDMARD vs those who are cycled to another JAKi.

The main conclusion — that JAKi, relative to bDMARDs for RA, is associated with an increased risk for herpes zoster but not other types of infections — is not a surprise, according to Floris A. van Gaalen, MD, PhD, a clinician and researcher in the Department of Rheumatology, Leiden University in the Netherlands.

“There are a number of risks with JAK inhibitors that have generated concern, but I think most clinicians are aware that they should be warning patients about herpes zoster,” said Dr. van Gaalen, who was not involved in the study. He believes the risk is sufficient to warrant a discussion with patients about taking the herpes zoster vaccine prior to treatment.

Relative Risk for Infection on JAKi Is Unclear

Although the greater risk for herpes zoster with JAKi vs bDMARDs is well established, the relative risk for other types of infections has been unclear, according to Mr. Aymon. One reason is that some, but not all, of the initial pivotal trials and safety studies associated JAKi with an increased risk for opportunistic infections, Mr. Aymon said.

The JAK-pot data, presented at the annual European Congress of Rheumatology, provide real-world data that shed light on this controversy, Mr. Aymon said.

Of the 20 national registries now providing data to JAK-pot, only 14 were included in this analysis. The study required data on infection rates from the time that JAKi became commercially available, which narrowed the data pool.

For this analysis, JAKi, which included tofacitinib (Xeljanz), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca), were compared separately and together with two groups of bDMARDs. One consisted of the tumor necrosis factor inhibitors (TNFi), infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab. The other was composed of bDMARDs with other modes of action (OMA). This group included abatacept, rituximab, sarilumab, and tocilizumab.
 

More Than 50,000 Exposures Included in Analysis

From the pooled registry, data were gathered from 13,374 courses of JAKi, 25,049 courses of TNFi, and 16,482 courses of OMA. There were some differences between these groups, including a significantly lower median age for those in the JAKi pool (57.1 years vs 58.3 and 60.5 years for TNFi and OMA, respectively) and median disease duration (8.3 years vs 11.0 and 11.9 years, respectively).

A greater proportion of patients on TNFi were naive to therapy (44.6%), compared with either JAKi (20.2%) or OMA (16.1%). More patients in the TNFi pool (60.0%) were also on concomitant therapy than those in the JAKi pool (49.5%) or the OMA pool (51.9%).

Other characteristics such as disease activity, body mass index, and percentage of smokers were comparable.

When TNFi was used as the reference, there were no significant differences in the rate of all infections, the rate of all infections excluding herpes zoster, and all serious infections. In all three groups, the incidence rates were numerically but not significantly lower in patients on JAKi vs OMA. With the exception of serious infections, for which the adjusted incidence of JAKi was 0.99 relative to TNFi, both JAKi and OMA had numerically higher incidence rate ratios than TNFi.
 

Herpes Zoster Risk on JAKi Is > Twofold Higher

Because the CIs overlapped in all cases, none of the differences were significant. The exception was herpes zoster. The 1.07 incidence rate ratio for OMA was not significantly different than the TNFi reference, but the 2.27 rate ratio for JAKi far exceeded either of the other two comparators (95% CI, 1.17-3.02).

In a separate analysis of patients at least 55 years of age with at least one cardiovascular risk factor, the numerical differences between groups were narrower and thus did not reach statistical significance, even for herpes zoster. Although the herpes zoster rate ratio was 1.62 for JAKi vs 1.23 for OMA (TNFi as the reference was 1.0), the CI for JAKi (0.86-3.03) overlapped both.

Based on a Poisson regression analysis, this study took into account a wide variety of variables, including age, disease activity, comorbidities, and tobacco use, Mr. Aymon said. He noted that the analyses were performed on data from each registry as well as with the pooled data, and the data were reasonably consistent.

Initially, the investigators had planned to evaluate differences between therapy groups, if any, for COVID-19 infection, but differences in the availability and use of vaccinations among the countries where the registries were maintained made this analysis too complicated to conduct.

Mr. Aymon reported no potential conflicts of interest, but some coauthors reported financial relationships with manufacturers of both bDMARDs and JAKi. Dr. van Gaalen reported financial relationships with AbbVie, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — In patients with rheumatoid arthritis (RA), Janus kinase inhibitors (JAKi) are associated with a substantially greater risk for herpes zoster, but the risk for other types of infections is about the same and often numerically lower relative to biologic disease-modifying antirheumatic drugs (bDMARDs), according to new data from the JAK-pot study.

“In the real world, we found no significantly greater risk of serious or nonserious infections, with the exception of herpes zoster,” said Romain Aymon, a statistician in the Department of Rheumatology at the University Hospital of Geneva, Switzerland.

Ted Bosworth/Medscape Medical News

This finding is the latest analysis generated by JAK-pot, a collaboration of 20 national registries to answer real-world questions about the efficacy and safety of JAKi in rheumatic diseases. These data have already been used to address such issues as relative rates of discontinuation for JAKi vs bDMARDs and to compare outcomes of RA patients who are switched to a bDMARD vs those who are cycled to another JAKi.

The main conclusion — that JAKi, relative to bDMARDs for RA, is associated with an increased risk for herpes zoster but not other types of infections — is not a surprise, according to Floris A. van Gaalen, MD, PhD, a clinician and researcher in the Department of Rheumatology, Leiden University in the Netherlands.

“There are a number of risks with JAK inhibitors that have generated concern, but I think most clinicians are aware that they should be warning patients about herpes zoster,” said Dr. van Gaalen, who was not involved in the study. He believes the risk is sufficient to warrant a discussion with patients about taking the herpes zoster vaccine prior to treatment.

Relative Risk for Infection on JAKi Is Unclear

Although the greater risk for herpes zoster with JAKi vs bDMARDs is well established, the relative risk for other types of infections has been unclear, according to Mr. Aymon. One reason is that some, but not all, of the initial pivotal trials and safety studies associated JAKi with an increased risk for opportunistic infections, Mr. Aymon said.

The JAK-pot data, presented at the annual European Congress of Rheumatology, provide real-world data that shed light on this controversy, Mr. Aymon said.

Of the 20 national registries now providing data to JAK-pot, only 14 were included in this analysis. The study required data on infection rates from the time that JAKi became commercially available, which narrowed the data pool.

For this analysis, JAKi, which included tofacitinib (Xeljanz), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca), were compared separately and together with two groups of bDMARDs. One consisted of the tumor necrosis factor inhibitors (TNFi), infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab. The other was composed of bDMARDs with other modes of action (OMA). This group included abatacept, rituximab, sarilumab, and tocilizumab.
 

More Than 50,000 Exposures Included in Analysis

From the pooled registry, data were gathered from 13,374 courses of JAKi, 25,049 courses of TNFi, and 16,482 courses of OMA. There were some differences between these groups, including a significantly lower median age for those in the JAKi pool (57.1 years vs 58.3 and 60.5 years for TNFi and OMA, respectively) and median disease duration (8.3 years vs 11.0 and 11.9 years, respectively).

A greater proportion of patients on TNFi were naive to therapy (44.6%), compared with either JAKi (20.2%) or OMA (16.1%). More patients in the TNFi pool (60.0%) were also on concomitant therapy than those in the JAKi pool (49.5%) or the OMA pool (51.9%).

Other characteristics such as disease activity, body mass index, and percentage of smokers were comparable.

When TNFi was used as the reference, there were no significant differences in the rate of all infections, the rate of all infections excluding herpes zoster, and all serious infections. In all three groups, the incidence rates were numerically but not significantly lower in patients on JAKi vs OMA. With the exception of serious infections, for which the adjusted incidence of JAKi was 0.99 relative to TNFi, both JAKi and OMA had numerically higher incidence rate ratios than TNFi.
 

Herpes Zoster Risk on JAKi Is > Twofold Higher

Because the CIs overlapped in all cases, none of the differences were significant. The exception was herpes zoster. The 1.07 incidence rate ratio for OMA was not significantly different than the TNFi reference, but the 2.27 rate ratio for JAKi far exceeded either of the other two comparators (95% CI, 1.17-3.02).

In a separate analysis of patients at least 55 years of age with at least one cardiovascular risk factor, the numerical differences between groups were narrower and thus did not reach statistical significance, even for herpes zoster. Although the herpes zoster rate ratio was 1.62 for JAKi vs 1.23 for OMA (TNFi as the reference was 1.0), the CI for JAKi (0.86-3.03) overlapped both.

Based on a Poisson regression analysis, this study took into account a wide variety of variables, including age, disease activity, comorbidities, and tobacco use, Mr. Aymon said. He noted that the analyses were performed on data from each registry as well as with the pooled data, and the data were reasonably consistent.

Initially, the investigators had planned to evaluate differences between therapy groups, if any, for COVID-19 infection, but differences in the availability and use of vaccinations among the countries where the registries were maintained made this analysis too complicated to conduct.

Mr. Aymon reported no potential conflicts of interest, but some coauthors reported financial relationships with manufacturers of both bDMARDs and JAKi. Dr. van Gaalen reported financial relationships with AbbVie, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — In patients with rheumatoid arthritis (RA), Janus kinase inhibitors (JAKi) are associated with a substantially greater risk for herpes zoster, but the risk for other types of infections is about the same and often numerically lower relative to biologic disease-modifying antirheumatic drugs (bDMARDs), according to new data from the JAK-pot study.

“In the real world, we found no significantly greater risk of serious or nonserious infections, with the exception of herpes zoster,” said Romain Aymon, a statistician in the Department of Rheumatology at the University Hospital of Geneva, Switzerland.

Ted Bosworth/Medscape Medical News

This finding is the latest analysis generated by JAK-pot, a collaboration of 20 national registries to answer real-world questions about the efficacy and safety of JAKi in rheumatic diseases. These data have already been used to address such issues as relative rates of discontinuation for JAKi vs bDMARDs and to compare outcomes of RA patients who are switched to a bDMARD vs those who are cycled to another JAKi.

The main conclusion — that JAKi, relative to bDMARDs for RA, is associated with an increased risk for herpes zoster but not other types of infections — is not a surprise, according to Floris A. van Gaalen, MD, PhD, a clinician and researcher in the Department of Rheumatology, Leiden University in the Netherlands.

“There are a number of risks with JAK inhibitors that have generated concern, but I think most clinicians are aware that they should be warning patients about herpes zoster,” said Dr. van Gaalen, who was not involved in the study. He believes the risk is sufficient to warrant a discussion with patients about taking the herpes zoster vaccine prior to treatment.

Relative Risk for Infection on JAKi Is Unclear

Although the greater risk for herpes zoster with JAKi vs bDMARDs is well established, the relative risk for other types of infections has been unclear, according to Mr. Aymon. One reason is that some, but not all, of the initial pivotal trials and safety studies associated JAKi with an increased risk for opportunistic infections, Mr. Aymon said.

The JAK-pot data, presented at the annual European Congress of Rheumatology, provide real-world data that shed light on this controversy, Mr. Aymon said.

Of the 20 national registries now providing data to JAK-pot, only 14 were included in this analysis. The study required data on infection rates from the time that JAKi became commercially available, which narrowed the data pool.

For this analysis, JAKi, which included tofacitinib (Xeljanz), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca), were compared separately and together with two groups of bDMARDs. One consisted of the tumor necrosis factor inhibitors (TNFi), infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab. The other was composed of bDMARDs with other modes of action (OMA). This group included abatacept, rituximab, sarilumab, and tocilizumab.
 

More Than 50,000 Exposures Included in Analysis

From the pooled registry, data were gathered from 13,374 courses of JAKi, 25,049 courses of TNFi, and 16,482 courses of OMA. There were some differences between these groups, including a significantly lower median age for those in the JAKi pool (57.1 years vs 58.3 and 60.5 years for TNFi and OMA, respectively) and median disease duration (8.3 years vs 11.0 and 11.9 years, respectively).

A greater proportion of patients on TNFi were naive to therapy (44.6%), compared with either JAKi (20.2%) or OMA (16.1%). More patients in the TNFi pool (60.0%) were also on concomitant therapy than those in the JAKi pool (49.5%) or the OMA pool (51.9%).

Other characteristics such as disease activity, body mass index, and percentage of smokers were comparable.

When TNFi was used as the reference, there were no significant differences in the rate of all infections, the rate of all infections excluding herpes zoster, and all serious infections. In all three groups, the incidence rates were numerically but not significantly lower in patients on JAKi vs OMA. With the exception of serious infections, for which the adjusted incidence of JAKi was 0.99 relative to TNFi, both JAKi and OMA had numerically higher incidence rate ratios than TNFi.
 

Herpes Zoster Risk on JAKi Is > Twofold Higher

Because the CIs overlapped in all cases, none of the differences were significant. The exception was herpes zoster. The 1.07 incidence rate ratio for OMA was not significantly different than the TNFi reference, but the 2.27 rate ratio for JAKi far exceeded either of the other two comparators (95% CI, 1.17-3.02).

In a separate analysis of patients at least 55 years of age with at least one cardiovascular risk factor, the numerical differences between groups were narrower and thus did not reach statistical significance, even for herpes zoster. Although the herpes zoster rate ratio was 1.62 for JAKi vs 1.23 for OMA (TNFi as the reference was 1.0), the CI for JAKi (0.86-3.03) overlapped both.

Based on a Poisson regression analysis, this study took into account a wide variety of variables, including age, disease activity, comorbidities, and tobacco use, Mr. Aymon said. He noted that the analyses were performed on data from each registry as well as with the pooled data, and the data were reasonably consistent.

Initially, the investigators had planned to evaluate differences between therapy groups, if any, for COVID-19 infection, but differences in the availability and use of vaccinations among the countries where the registries were maintained made this analysis too complicated to conduct.

Mr. Aymon reported no potential conflicts of interest, but some coauthors reported financial relationships with manufacturers of both bDMARDs and JAKi. Dr. van Gaalen reported financial relationships with AbbVie, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Results from the phase 3 SELECT-GCA study showed that the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) induces significant and sustained remission in people with new-onset or relapsing giant cell arteritis (GCA).

The primary endpoint of sustained remission — the absence of GCA signs or symptoms from weeks 12 to 52 together with adherence to a steroid-tapering regimen — occurred in 46% of 210 individuals randomly assigned to treatment treated with a once-daily 15-mg dose of upadacitinib and 29% of 105 randomly assigned to placebo (P = .0019).

Nine of the 11 secondary endpoints were also positive for upadacitinib 15 mg vs placebo, and no new safety concerns were identified in a late-breaking abstract presented at the at the annual European Congress of Rheumatology.
 

First JAK Trial in GCA

This is the first trial to look at the use of a JAK inhibitor for the treatment of GCA, and it is addressing a real unmet need, the presenting study investigator Daniel Blockmans, MD, PhD, of University Hospitals Leuven in Belgium, told this news organization.

Glucocorticoids remain the mainstay of treatment, and tocilizumab has been licensed for use, but people don’t always get better or can relapse, he explained.

“I have the impression that these only suppress the disease but do not cure it,” Dr. Blockmans said, adding that “patients get very well soon after these treatments are started, but there are more and more reports that there is a kind of smoldering vasculitis that exists, and this can lead to dilatation of the aorta.”

Upadacitinib inhibits two JAK-dependent cytokines, interleukin 6 and interferon gamma, which have been implicated in the pathogenesis of GCA. The latter could be particularly important, Dr. Blockmans suggested.
 

Study Details

SELECT-GCA is an ongoing multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of upadacitinib vs placebo in patients with GCA.

A total of 428 patients have been included: 210 were randomly allocated to treatment with upadacitinib 15 mg, 105 to upadacitinib 7.5 mg, and 105 to placebo. The inclusion of the lower “minimally effective” upadacitinib dose was a requirement of the regulatory authorities, Dr. Blockmans said; the licensed dose in rheumatoid arthritis (RA) is 15 mg.

Dr. Blockmans reported data from the first 52 weeks of the trial during which all patients underwent glucocorticoid tapering — 26 weeks for upadacitinib and 52 weeks for placebo.

No imaging was done in this trial, which Dr. Blockmans said should be considered for future studies.
 

Secondary Endpoints

One of the key secondary endpoints was sustained complete remission, defined as sustained remission plus a normalized erythrocyte sedimentation rate to ≤ 30 mm/h and reducing high-sensitivity C-reactive protein to < 1 mg/dL.

Sustained complete remission occurred in 37% and 16% of patients treated with upadacitinib 15 mg and placebo, respectively (P < .0001).

Additionally, a significantly lower proportion of upadacitinib 15 mg- than placebo-treated patients experienced at least one disease flare through week 52 (34% vs 56%, P = .0014).

Other positive secondary endpoints for upadacitinib 15 mg vs placebo out to week 52 were the number of disease flares per patient, cumulative glucocorticoid exposure, and complete remission (also at week 24).

And significant changes in SF-36 and FACIT-Fatigue from baseline to week 52 were seen for upadacitinib 15 mg.

The only secondary endpoints not showing a clear benefit for upadacitinib 15 mg were the changes in the Treatment Satisfaction Questionnaire for Medication at 52 weeks and the rate of glucocorticoid-related adverse events through week 52.

As for the 7.5-mg dose of upadacitinib, neither the primary nor secondary endpoints were significantly better vs placebo.
 

‘Life-Changing’

The study’s findings could be “really life-changing” for patients with this type of vasculitis if upadacitinib gets approval for use in this indication, Milena Bond, MD, PhD, of Brunico Hospital in Italy, told this news organization at the meeting.

“Unfortunately, nowadays, we still have only a few options for treating these patients,” she said. “So, this drug could be really, really important.”

Dr. Bond added: “The data ... also shows there is a very good safety profile, which was a main concern given the class of the drug. So, I’m very positive about this treatment and very excited to see the preliminary results.”

After his presentation, Dr. Blockmans said, “Of course, if we already had an ideal treatment for GCA, there would be no need for a JAK inhibitor, but I don’t think that steroid treatment or tocilizumab treatment is the ideal treatment.”
 

Judicious Use Still Warranted

Upadacitinib still needs to be used cautiously, following appropriate guidance from the European Medicines Agency (EMA) and the US Food and Drug Administration.

Dr. Bond said: “It is not advised to use to the drug when people are older than 65 years old,” according to the EMA, for example, and “given the rules that we have, I would not use this drug as a first-line treatment. We do not do that for rheumatoid arthritis.”

But, she added, “As for arthritis, when you fail treating patients with the other alternatives, you could use this drug, and you have to discuss risks with the patients.”

Dr. Blockmans reported there had been no increased risk for major adverse cardiovascular events or venous thromboembolism associated with upadacitinib relative to placebo in the population of patients studied, and he pointed out that they had a much higher risk for these events than perhaps an RA population.

He said: “It’s effective, and it’s apparently safe in these older people, despite what we heard about tofacitinib in the ORAL [Surveillance] study; we didn’t see these problems here in this elderly population.”

The SELECT-GCA trial was funded by AbbVie, and the company participated in all aspects of the study, including its design, conduct, interpretation of data, and reporting. Dr. Blockmans received no funding or other honoraria from the company but reported a research grant from Roche and consulting fees from GlaxoSmithKline. Most of his coauthors reported financial relationships with AbbVie, and some are employees of the company. Dr. Bond reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

BOSTON — Men who stop using performance-enhancing anabolic-androgenic steroids (AAS) experience significant depression, anxiety, and diminished sexual function within the first year after quitting, new research found.

The data suggest that monitoring these men and, pending clinical trial evidence, intervening to minimize these effects could help prevent recidivism, Bonnie Grant, MBBS, a clinical research fellow at Imperial College London, London, England, told this news organization.

“Nothing has actually been studied in proper randomized controlled trials … but I think there’s going to be a role for medicine alongside psychological treatment … Clinicians often see men who have stopped [taking steroids] who report feeling low in mood … a lot of these men will just restart taking them again,” she said.

Anabolic steroids taken exogenously suppress the hypothalamic-pituitary-gonadal system, thereby suppressing endogenous testosterone secretion. While AAS do enhance muscle-building, they can also lead to enlarged hearts, hypertension, and infertility. Most of these are reversible if the man stops taking the AAS.

However, after stopping, the testosterone levels can take up to a year to return to normal. During that time, the man can experience symptoms including low libido, erectile dysfunction, low mood, and fatigue. This leads to a dependence syndrome in about 30%. About 65% of men who stop taking anabolic steroids will restart taking them within the first year, Dr. Grant said in presenting her findings at the annual meeting of the Endocrine Society.

Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “One question is, if you intervene with an antidepressant, will that prevent the people from relapsing and going back to using? I think that’s certainly something that would need to be explored and tested.”

Dr. Hayes also noted that fertility problems may lead some men to decide to stop using the steroids. “That can be a strong motivator. If you have a motivated patient, then you add in an antidepressant or anxiolytic or link the patients with mental health services. I think that would definitely be beneficial and definitely something we need to address and see if it is worthwhile doing.”

Dr. Grant presented data from her group’s cross-sectional, observational study. Of a total 245 men, 116 were current AAS users, 84 were previous AAS users who had quit within the past year, and 45 had never used them. All completed extensive questionnaires about their substance use, mood, sexual function, and anxiety. They had morning blood tests, and urine samples were taken for toxicology testing.

The three groups didn’t differ by age (most were in their mid-30s) or ethnicity (most were White). However, the proportion who self-reported psychiatric diagnoses (mostly depression or anxiety) was significantly higher among both the current (29%) and past (25%) AAS users than among the never users (6.6%), with P = .0094.

Dr. Hayes commented, “One of the drawbacks of this study was they didn’t have baseline data. But it would make sense, I think, that the incidence of depression and anxiety was higher in the people who went on to use anabolic steroids.”

Use of other illicit drugs — mostly cocaine and cannabis — was also higher among the past (40.5%) and current (47.4%) AAS users than among the nonusers (17.7%), P = .0025.

Not surprisingly, total testosterone levels were much higher in current AAS users (62.8 nmol/L) than in past users (20.1 nmol/L) and nonusers (20.0 nmol/L), P < .001. Levels of luteinizing hormone (LH), follicle-stimulating hormone, and sex hormone-binding globulin were significantly lower in the current AAS users than in the other two groups, while estradiol levels were significantly higher (all P < .001).

There were no differences in total testosterone between the never users and previous users. However, about 25% of the men who stopped continued to have lower-than-normal testosterone levels, Dr. Grant noted.

Depression scores, as assessed by the Beck Depression Inventory-II, were highest in men who stopped using AAS, and lowest in the never users. Moderate to severe depression was present in 20% of the men who stopped using AAS, 6% of current users, and none of the nonusers.

In multivariable analysis, having a prior psychiatric diagnosis increased the risk for current depression on the Beck inventory by twofold in the current AAS users (P = .001) and threefold in the past users (P < .001). “Interestingly, testosterone levels were not associated with depression,” she noted.

Sexual function, as measured by the International Index of Erectile Function (IIEF) 15, was significantly worse among those who had stopped using AAS compared with current users and nonusers (P = .023). At the same time, total testosterone levels were only weakly correlated with IIEF scores.

In multivariate analysis, higher LH levels were associated with worse sexual function (P = .01).

Anxiety, as measured by the General Anxiety Disorder-7 assessment, was higher in previous users than in never users. Overall, 12% of the previous users had moderate or severe anxiety vs just 2% of nonusers.

The next step in the research will be to examine the urine toxicology for AAS and other illicit substances, Dr. Grant said.

“We’re hoping this information will allow for future studies to be developed to design treatments, which will help millions of men worldwide to stop and stay off anabolic steroids,” she concluded.

Dr. Grant and Dr. Hayes had no disclosures.

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

BOSTON — Men who stop using performance-enhancing anabolic-androgenic steroids (AAS) experience significant depression, anxiety, and diminished sexual function within the first year after quitting, new research found.

The data suggest that monitoring these men and, pending clinical trial evidence, intervening to minimize these effects could help prevent recidivism, Bonnie Grant, MBBS, a clinical research fellow at Imperial College London, London, England, told this news organization.

“Nothing has actually been studied in proper randomized controlled trials … but I think there’s going to be a role for medicine alongside psychological treatment … Clinicians often see men who have stopped [taking steroids] who report feeling low in mood … a lot of these men will just restart taking them again,” she said.

Anabolic steroids taken exogenously suppress the hypothalamic-pituitary-gonadal system, thereby suppressing endogenous testosterone secretion. While AAS do enhance muscle-building, they can also lead to enlarged hearts, hypertension, and infertility. Most of these are reversible if the man stops taking the AAS.

However, after stopping, the testosterone levels can take up to a year to return to normal. During that time, the man can experience symptoms including low libido, erectile dysfunction, low mood, and fatigue. This leads to a dependence syndrome in about 30%. About 65% of men who stop taking anabolic steroids will restart taking them within the first year, Dr. Grant said in presenting her findings at the annual meeting of the Endocrine Society.

Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “One question is, if you intervene with an antidepressant, will that prevent the people from relapsing and going back to using? I think that’s certainly something that would need to be explored and tested.”

Dr. Hayes also noted that fertility problems may lead some men to decide to stop using the steroids. “That can be a strong motivator. If you have a motivated patient, then you add in an antidepressant or anxiolytic or link the patients with mental health services. I think that would definitely be beneficial and definitely something we need to address and see if it is worthwhile doing.”

Dr. Grant presented data from her group’s cross-sectional, observational study. Of a total 245 men, 116 were current AAS users, 84 were previous AAS users who had quit within the past year, and 45 had never used them. All completed extensive questionnaires about their substance use, mood, sexual function, and anxiety. They had morning blood tests, and urine samples were taken for toxicology testing.

The three groups didn’t differ by age (most were in their mid-30s) or ethnicity (most were White). However, the proportion who self-reported psychiatric diagnoses (mostly depression or anxiety) was significantly higher among both the current (29%) and past (25%) AAS users than among the never users (6.6%), with P = .0094.

Dr. Hayes commented, “One of the drawbacks of this study was they didn’t have baseline data. But it would make sense, I think, that the incidence of depression and anxiety was higher in the people who went on to use anabolic steroids.”

Use of other illicit drugs — mostly cocaine and cannabis — was also higher among the past (40.5%) and current (47.4%) AAS users than among the nonusers (17.7%), P = .0025.

Not surprisingly, total testosterone levels were much higher in current AAS users (62.8 nmol/L) than in past users (20.1 nmol/L) and nonusers (20.0 nmol/L), P < .001. Levels of luteinizing hormone (LH), follicle-stimulating hormone, and sex hormone-binding globulin were significantly lower in the current AAS users than in the other two groups, while estradiol levels were significantly higher (all P < .001).

There were no differences in total testosterone between the never users and previous users. However, about 25% of the men who stopped continued to have lower-than-normal testosterone levels, Dr. Grant noted.

Depression scores, as assessed by the Beck Depression Inventory-II, were highest in men who stopped using AAS, and lowest in the never users. Moderate to severe depression was present in 20% of the men who stopped using AAS, 6% of current users, and none of the nonusers.

In multivariable analysis, having a prior psychiatric diagnosis increased the risk for current depression on the Beck inventory by twofold in the current AAS users (P = .001) and threefold in the past users (P < .001). “Interestingly, testosterone levels were not associated with depression,” she noted.

Sexual function, as measured by the International Index of Erectile Function (IIEF) 15, was significantly worse among those who had stopped using AAS compared with current users and nonusers (P = .023). At the same time, total testosterone levels were only weakly correlated with IIEF scores.

In multivariate analysis, higher LH levels were associated with worse sexual function (P = .01).

Anxiety, as measured by the General Anxiety Disorder-7 assessment, was higher in previous users than in never users. Overall, 12% of the previous users had moderate or severe anxiety vs just 2% of nonusers.

The next step in the research will be to examine the urine toxicology for AAS and other illicit substances, Dr. Grant said.

“We’re hoping this information will allow for future studies to be developed to design treatments, which will help millions of men worldwide to stop and stay off anabolic steroids,” she concluded.

Dr. Grant and Dr. Hayes had no disclosures.

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

BOSTON — Men who stop using performance-enhancing anabolic-androgenic steroids (AAS) experience significant depression, anxiety, and diminished sexual function within the first year after quitting, new research found.

The data suggest that monitoring these men and, pending clinical trial evidence, intervening to minimize these effects could help prevent recidivism, Bonnie Grant, MBBS, a clinical research fellow at Imperial College London, London, England, told this news organization.

“Nothing has actually been studied in proper randomized controlled trials … but I think there’s going to be a role for medicine alongside psychological treatment … Clinicians often see men who have stopped [taking steroids] who report feeling low in mood … a lot of these men will just restart taking them again,” she said.

Anabolic steroids taken exogenously suppress the hypothalamic-pituitary-gonadal system, thereby suppressing endogenous testosterone secretion. While AAS do enhance muscle-building, they can also lead to enlarged hearts, hypertension, and infertility. Most of these are reversible if the man stops taking the AAS.

However, after stopping, the testosterone levels can take up to a year to return to normal. During that time, the man can experience symptoms including low libido, erectile dysfunction, low mood, and fatigue. This leads to a dependence syndrome in about 30%. About 65% of men who stop taking anabolic steroids will restart taking them within the first year, Dr. Grant said in presenting her findings at the annual meeting of the Endocrine Society.

Asked to comment, session moderator Frances Hayes, MBBCh, associate clinical chief of the Division of Reproductive Endocrinology at Massachusetts General Hospital, Boston, said, “One question is, if you intervene with an antidepressant, will that prevent the people from relapsing and going back to using? I think that’s certainly something that would need to be explored and tested.”

Dr. Hayes also noted that fertility problems may lead some men to decide to stop using the steroids. “That can be a strong motivator. If you have a motivated patient, then you add in an antidepressant or anxiolytic or link the patients with mental health services. I think that would definitely be beneficial and definitely something we need to address and see if it is worthwhile doing.”

Dr. Grant presented data from her group’s cross-sectional, observational study. Of a total 245 men, 116 were current AAS users, 84 were previous AAS users who had quit within the past year, and 45 had never used them. All completed extensive questionnaires about their substance use, mood, sexual function, and anxiety. They had morning blood tests, and urine samples were taken for toxicology testing.

The three groups didn’t differ by age (most were in their mid-30s) or ethnicity (most were White). However, the proportion who self-reported psychiatric diagnoses (mostly depression or anxiety) was significantly higher among both the current (29%) and past (25%) AAS users than among the never users (6.6%), with P = .0094.

Dr. Hayes commented, “One of the drawbacks of this study was they didn’t have baseline data. But it would make sense, I think, that the incidence of depression and anxiety was higher in the people who went on to use anabolic steroids.”

Use of other illicit drugs — mostly cocaine and cannabis — was also higher among the past (40.5%) and current (47.4%) AAS users than among the nonusers (17.7%), P = .0025.

Not surprisingly, total testosterone levels were much higher in current AAS users (62.8 nmol/L) than in past users (20.1 nmol/L) and nonusers (20.0 nmol/L), P < .001. Levels of luteinizing hormone (LH), follicle-stimulating hormone, and sex hormone-binding globulin were significantly lower in the current AAS users than in the other two groups, while estradiol levels were significantly higher (all P < .001).

There were no differences in total testosterone between the never users and previous users. However, about 25% of the men who stopped continued to have lower-than-normal testosterone levels, Dr. Grant noted.

Depression scores, as assessed by the Beck Depression Inventory-II, were highest in men who stopped using AAS, and lowest in the never users. Moderate to severe depression was present in 20% of the men who stopped using AAS, 6% of current users, and none of the nonusers.

In multivariable analysis, having a prior psychiatric diagnosis increased the risk for current depression on the Beck inventory by twofold in the current AAS users (P = .001) and threefold in the past users (P < .001). “Interestingly, testosterone levels were not associated with depression,” she noted.

Sexual function, as measured by the International Index of Erectile Function (IIEF) 15, was significantly worse among those who had stopped using AAS compared with current users and nonusers (P = .023). At the same time, total testosterone levels were only weakly correlated with IIEF scores.

In multivariate analysis, higher LH levels were associated with worse sexual function (P = .01).

Anxiety, as measured by the General Anxiety Disorder-7 assessment, was higher in previous users than in never users. Overall, 12% of the previous users had moderate or severe anxiety vs just 2% of nonusers.

The next step in the research will be to examine the urine toxicology for AAS and other illicit substances, Dr. Grant said.

“We’re hoping this information will allow for future studies to be developed to design treatments, which will help millions of men worldwide to stop and stay off anabolic steroids,” she concluded.

Dr. Grant and Dr. Hayes had no disclosures.

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

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.