Rheumatology News

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.

Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.

Viktor Cap/Thinkstock

Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
 

The trial

The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.

A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.

The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.

The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO_{2 max}) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).

Following HIIT, a statistically significant difference was observed in VO_{2 max} (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO_{2 max} between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO_{2 max} between the groups (3.2 mL/kg per min; P < .01).

Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
 

Long-lasting effects

Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”

There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.

Ms. Norden and coauthors report no relevant financial relationships.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

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

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

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

AT EULAR 2023

MILAN – Safety considerations, particularly regarding the use of Janus kinase (JAK) inhibitors, are of utmost importance in the 2023 update to recommendations for managing psoriatic arthritis (PsA) by the European Alliance of Associations for Rheumatology (EULAR). Additionally, the selection of therapy should now take into account the complete clinical presentation, explicitly considering nonmusculoskeletal manifestations.

Safety considerations with JAK inhibitors

Expanding on the existing six overarching principles from the 2019 recommendations, the PsA EULAR recommendations now introduce a seventh principle: “The choice of treatment should consider safety considerations regarding individual modes of action to optimize the benefit-risk profile.”

This addition was prompted by recent safety data on JAK inhibitors, which revealed serious potential side effects, such as heart attacks, blood clots, cancer, and severe infections, that recently prompted the European Medicines Agency to restrict their use. As indicated by the new principle, safety considerations have been incorporated into several recommendations.

For instance, in the context of peripheral arthritis, JAK inhibitors may now be considered if there is an inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate, sulfasalazine, or leflunomide, and at least one biologic DMARD (bDMARD).

Alternatively, JAK inhibitors may be utilized when bDMARDs are not suitable for other reasons. However, EULAR now emphasizes caution whenever JAK inhibitors are mentioned. Specifically, “careful consideration is necessary for patients aged 65 or above, current or past long-time smokers, individuals with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, those with other malignancy risk factors, or individuals with a known risk for venous thromboembolism.”
 

Consider nonmusculoskeletal manifestations in treatment decisions

In another significant update, EULAR now recommends that the choice of therapy should also consider nonmusculoskeletal manifestations associated with PsA. “There is a notable shift in perspective here,” Dr. Gossec told this news organization. Clinically relevant skin involvement should prompt the use of IL-17A or IL-17A/F or IL-23 or IL-12/23 inhibitors, while uveitis should be treated with tumor necrosis factor (TNF) inhibitors.

In the case of inflammatory bowel disease, EULAR advises the use of anti-TNF agents, IL-12/23 or IL-23 inhibitors, or a JAK inhibitor. The recommended course of action within each treatment category is not ranked in order of preference, but EULAR emphasizes the importance of following EMA recommendations and considering safety.
 

Systemic glucocorticoids removed

Certain medications have been removed from the recommendations, reflecting the heightened focus on treatment safety. The use of systemic glucocorticoids as adjunctive therapy is no longer recommended. “We always had reservations about their use, and now we have eliminated them. We are aware that they are still utilized, with 30% of patients in Germany, for instance, receiving low doses of glucocorticoids. However, the long-term efficacy/safety balance of glucocorticoids is unfavorable in any disease, particularly in patients with psoriatic arthritis and multiple comorbidities,” Dr. Gossec explained.

NSAIDs and local glucocorticoids are now limited to specific patient populations, namely those affected by oligoarthritis without poor prognostic factors, entheseal disease, or predominant axial disease. Their use should be short-term, generally no longer than 4 weeks. Polyarthritis or oligoarthritis with poor prognostic factors should instead be treated directly with csDMARDs.
 

No specific biologic treatment order recommended for peripheral arthritis

Regarding patients with peripheral arthritis, recent efficacy data have led EULAR to refrain from recommending any specific order of preference for the use of bDMARDs, which encompass TNF inhibitors and drugs targeting the IL-17 and IL-12/23 pathways. “We lack the data to propose an order of preference in patients with peripheral arthritis. Different classes of molecules exhibit efficacy in joint inflammation, generally resulting in a 50% response rate and similar overall effects,” said Dr. Gossec, referencing head-to-head trials between biologics that yielded very comparable results, such as the EXCEED trial or SPIRIT-H2H trial.

The updated recommendations now consider two IL-23p19 inhibitors, guselkumab (Tremfya) and risankizumab (Skyrizi), the JAK inhibitor upadacitinib (Rinvoq), and the very recently EMA-approved bimekizumab (Bimzelx), an IL-17A/F double inhibitor.

The recommendation for patients with mono- or oligoarthritis and poor prognostic factors now aligns with the previous recommendations for polyarthritis: A csDMARD should be initiated promptly, with a preference for methotrexate if significant skin involvement is present. New data suggest that methotrexate may be beneficial for enthesitis, achieving resolution in approximately 30% of patients. When considering treatment options, JAK inhibitors may also be taken into account, with safety considerations in mind.

In cases of clinically relevant axial disease and an inadequate response to NSAIDs, therapy with an IL-17A inhibitor, a TNF inhibitor, an IL-17A/F inhibitor, or a JAK inhibitor may be considered. This approach now aligns with the most recent axial spondyloarthritis recommendation from EULAR and the Assessment of SpondyloArthritis international Society (ASAS).
 

Which disease manifestation to treat first?

During the discussion, chairwoman Uta Kiltz, MD, PhD, a rheumatologist at Rheumatism Center Ruhrgebiet, Herne, Germany, and clinical lecturer at Ruhr University Bochum, inquired about identifying the primary manifestation to guide the course of action.

“Psoriatic arthritis is highly heterogeneous, and determining the predominant manifestation is sometimes challenging,” Dr. Gossec said. “However, we believe that a certain order of preference is necessary when making treatment decisions. Starting with peripheral arthritis, which can lead to structural damage, allows for treatment selection based on that aspect. If peripheral arthritis is not present, attention should be directed towards axial disease, ensuring the presence of actual inflammation rather than solely axial pain, as mechanical origin axial pain can occur due to the patient’s age.”

David Liew, MBBS, PhD, consultant rheumatologist and clinical pharmacologist at Austin Health in Melbourne, commented on the update to this news organization: “We are fortunate to have a wide range of targeted therapy options for psoriatic arthritis, and these guidelines reflect this abundance of choices. They emphasize the importance of selecting therapies based on specific disease manifestations and tailoring care to each patient’s unique type of psoriatic arthritis. It’s worth noting that some changes in these guidelines were influenced by regulatory changes following ORAL Surveillance. In an era of numerous options, we can afford to be selective at times.”

Regarding safety concerns and JAK inhibitors, Dr. Liew added: “It is not surprising to see these guidelines impose certain restrictions on the use of JAK inhibitors, especially in psoriatic arthritis, where other therapies offer distinct advantages. Until high-quality evidence convincingly points away from a class effect, we can expect to see similar provisions in many more guidelines.”

Many of the recommendations’ authors report financial relationships with one or more pharmaceutical companies. These include AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Chugai, Galapagos, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, R-Pharma, Regeneron, Roche, Sandoz, Sanofi, Takeda, UCB, and Viatris.

EULAR funded the development of the recommendations.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

Researchers may use artificial intelligence (AI) language models such as ChatGPT to write and revise scientific manuscripts, according to a new announcement from the International Committee of Medical Journal Editors. These tools should not be listed as authors, and researchers must denote how AI-assisted technologies were used, the committee said.

These new guidelines are the latest effort for medical journals to define policies for using these large-scale language models (LLMs) in scientific publication. While these AI-assisted tools can help with tasks such as writing, analyzing data, catching mistakes, and much more, they are also prone to errors, noted Casey Greene, PhD, a professor of biomedical informatics at the University of Colorado at Denver, Aurora. It is also not totally clear how information is stored and processed in these kinds of tools, and who has access to that information, he noted.

At the same time, experts argue that these AI tools could have a positive impact on the field by limiting some of the linguistic disparities in scientific publishing as well as alleviating the burden of some monotonous or mechanical tasks that come along with manuscript writing.

What experts can agree on, though, is that the use of AI tools is here to stay. “This is going to become a common tool,” Dr. Greene said. “I don’t think there’s a way out of that at this point.”
 

A change in medical publishing

OpenAI released ChatGPT in November 2022. In its own words, ChatGPT is “a deep learning model that has been trained on a massive amount of text data to understand and generate humanlike text.” Enter a question or a prompt, and it will respond. For example, when asked how the AI tool can be used in scientific publishing, ChatGPT responded:

“ChatGPT can aid scientific publishing by generating ideas, clarifying concepts, conducting preliminary literature reviews, providing proofreading and editing suggestions, and assisting with outlining and organizing scientific papers. However, it should be used as a supportive tool alongside domain expertise and validation from trusted scientific sources.”

Just a few months after ChatGPT became available, researchers began using this tool in their own work. One individual, Som Biswas, MD, a radiologist at the University of Tennessee Health Science Center in Memphis, reportedly used ChatGPT to author 16 scientific articles in just 4 months, according to the Daily Beast. Five of these articles have been published in four different journals. Dr. Biswas declined to be interviewed for this article.

There were also reports of papers with ChatGPT as one of the listed authors, which sparked backlash. In response, JAMA, Nature, and Science all published editorials in January outlining their policies for using ChatGPT and other large language models in the scientific authoring process. Editors from the journals of the American College of Cardiology and the American College of Rheumatology also updated their policies to reflect the influence of AI authoring tools.

The consensus is that AI has no place on the author byline.

“We think that’s not appropriate, because coauthorship means that you are taking responsibility for the analysis and the generation of data that are included in a manuscript. A machine that is dictated by AI can’t take responsibility,” said Daniel Solomon, MD, MPH, a rheumatologist at Brigham and Women’s Hospital, Boston, and the editor in chief of the ACR journal Arthritis & Rheumatology.
 

Issues with AI

One of the big concerns around using AI in writing is that it can generate text that seems plausible but is untrue or not supported by data. For example, Dr. Greene and colleague Milton Pividori, PhD, also of the University of Colorado, were writing a journal article about new software they developed that uses a large language model to revise scientific manuscripts.

“We used the same software to revise that article and at one point, it added a line that noted that the large language model had been fine-tuned on a data set of manuscripts from within the same field. This makes a lot of sense, and is absolutely something you could do, but was not something that we did,” Dr. Greene said. “Without a really careful review of the content, it becomes possible to invent things that were not actually done.”

In another case, ChatGPT falsely stated that a prominent law professor had been accused of sexual assault, citing a Washington Post article that did not exist.

“We live in a society where we are extremely concerned about fake news,” Dr. Pividori added, “and [these kinds of errors] could certainly exacerbate that in the scientific community, which is very concerning because science informs public policy.”

Another issue is the lack of transparency around how large language models like ChatGPT process and store data used to make queries.

“We have no idea how they are recording all the prompts and things that we input into ChatGPT and their systems,” Dr. Pividori said.

OpenAI recently addressed some privacy concerns by allowing users to turn off their chat history with the AI chatbot, so conversations cannot be used to train or improve the company’s models. But Dr. Greene noted that the terms of service “still remain pretty nebulous.”

Dr. Solomon is also concerned with researchers using these AI tools in authoring without knowing how they work. “The thing we are really concerned about is that fact that [LLMs] are a bit of a black box – people don’t really understand the methodologies,” he said.
 

A positive tool?

But despite these concerns, many think that these types of AI-assisted tools could have a positive impact on medical publishing, particularly for researchers for whom English is not their first language, noted Catherine Gao, MD, a pulmonary and critical care instructor at Northwestern University, Chicago. She recently led research comparing scientific abstracts written by ChatGPT and real abstracts and discovered that reviewers found it “surprisingly difficult” to differentiate the two.

“The majority of research is published in English,” she said in an email. “Responsible use of LLMs can potentially reduce the burden of writing for busy scientists and improve equity for those who are not native English speakers.”

Dr. Pividori agreed, adding that as a non-native English speaker, he spends much more time working on the structure and grammar of sentences when authoring a manuscript, compared with people who speak English as a first language. He noted that these tools can also be used to automate some of the more monotonous tasks that come along with writing manuscripts and allow researchers to focus on the more creative aspects.

In the future, “I want to focus more on the things that only a human can do and let these tools do all the rest of it,” he said.
 

New rules

But despite how individual researchers feel about LLMs, they agree that these AI tools are here to stay.

“I think that we should anticipate that they will become part of the medical research establishment over time, when we figure out how to use them appropriately,” Dr. Solomon said.

While the debate of how to best use AI in medical publications will continue, journal editors agree that all authors of a manuscript are solely responsible for content in articles that used AI-assisted technology.

“Authors should carefully review and edit the result because AI can generate authoritative-sounding output that can be incorrect, incomplete, or biased,” the ICMJE guidelines state. “Authors should be able to assert that there is no plagiarism in their paper, including in text and images produced by the AI.” This includes appropriate attribution of all cited materials.

The committee also recommends that authors write in both the cover letter and submitted work how AI was used in the manuscript writing process. Recently updated guidelines from the World Association of Medical Editors recommend that all prompts used to generate new text or analytical work should be provided in submitted work. Dr. Greene also noted that if authors used an AI tool to revise their work, they can include a version of the manuscript untouched by LLMs.

It is similar to a preprint, he said, but rather than publishing a version of a paper prior to peer review, someone is showing a version of a manuscript before it was reviewed and revised by AI. “This type of practice could be a path that lets us benefit from these models,” he said, “without having the drawbacks that many are concerned about.”

Dr. Solomon has financial relationships with AbbVie, Amgen, Janssen, CorEvitas, and Moderna. Both Dr. Greene and Dr. Pividori are inventors in the U.S. Provisional Patent Application No. 63/486,706 that the University of Colorado has filed for the “Publishing Infrastructure For AI-Assisted Academic Authoring” invention with the U.S. Patent and Trademark Office. Dr. Greene and Dr. Pividori also received a grant from the Alfred P. Sloan Foundation to improve their AI-based manuscript revision tool. Dr. Gao reported no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

MILAN – Rheumatic disease is not considered a significant risk factor for long COVID, according to the findings of a Dutch prospective cohort study presented at the annual European Congress of Rheumatology.

Although more patients with inflammatory rheumatic diseases (iRD) report symptoms resembling long COVID, the data suggest that many of these symptoms can be attributed to the underlying rheumatic disease. “Overall, we find the data quite reassuring,” said Laura Boekel, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center.

The results were also published in The Lancet Rheumatology.

The risk of developing long COVID after infection with the Omicron variant appeared to be higher in patients with iRD, with 21% meeting the criteria set by the World Health Organization, compared with 13% of healthy individuals (odds ratio, 1.58; P = .037). Fatigue and loss of fitness were the most common long COVID symptoms reported by both iRD patients and controls. However, the difference in risk decreased after accounting for factors that are significantly associated with an increased risk for long COVID, such as body mass index and the severity of the acute COVID-19 infection (adjusted OR, 1.46; P = .081). The duration of symptoms did not show a statistically significant difference.

Kim Lauper, MD, University of Geneva, who chaired the session in which Ms. Boekel reported the study, said in an interview that the data should be interpreted with caution. “The data demonstrate that rheumatic disease itself is not a risk factor for long COVID. However, patients with rheumatic diseases are at a higher risk of severe disease, which in turn increases the likelihood of long COVID. Therefore, as a population, these patients are more susceptible to long COVID overall.”

Moreover, irrespective of their previous COVID-19 infection status, iRD patients often exhibit symptoms similar to those of long COVID even without a prior COVID-19 infection. (There was no history of COVID-19 in 21% of iRD patients vs. 11% of controls.) This suggests that some of the reported long COVID symptoms may actually be clinical manifestations of the underlying rheumatic disease, thereby complicating the diagnosis of long COVID in this population. The study employed the WHO definition of long COVID, which includes persistent symptoms lasting at least 8 weeks, beginning within 3 months of a confirmed SARS-CoV-2 infection, and that cannot be attributed to an alternative diagnosis. However, the data presented in Milan indicate that the WHO definition “is not well suited for patients with iRD due to significant overlap in symptoms and features,” Ms. Boekel concluded.

The cases of Omicron COVID-19 were identified during Jan. 1–April 25, 2022, among iRD patients recruited from the Amsterdam Rheumatology and Immunology Center. The population with confirmed SARS-CoV-2 Omicron infection during this period was monitored for long COVID. The total number of patients included in the study consisted of 77 iRD patients and 23 healthy controls. When asked about the potential risk of selection bias in the survey, Ms. Boekel stated that only approximately 8% of participants declined to respond, and the nonresponders were comparable with the respondents. She concluded that “the risk of selection bias is minimal.”

In an editorial published in The Lancet Rheumatology, Leonard H. Calabrese, DO, Cleveland Clinic, provided his insights on the findings. He emphasized that, “at present, long COVID remains an important reality that significantly impacts the lives of millions of individuals, yet it remains incompletely defined. ... These limitations in defining cases should not in any way undermine the experiences of those suffering from long COVID. Instead, they should serve as a reminder that, at this stage of the pandemic, we unfortunately still lack validated classification criteria for long COVID. It is crucial to include non–SARS-CoV-2–infected controls in all studies to further enhance our understanding.”

Ms. Boekel and coauthors, as well as Dr. Lauper and Dr. Calabrese, reported no relevant financial relationships.

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

MILAN – Rheumatic disease is not considered a significant risk factor for long COVID, according to the findings of a Dutch prospective cohort study presented at the annual European Congress of Rheumatology.

Although more patients with inflammatory rheumatic diseases (iRD) report symptoms resembling long COVID, the data suggest that many of these symptoms can be attributed to the underlying rheumatic disease. “Overall, we find the data quite reassuring,” said Laura Boekel, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center.

The results were also published in The Lancet Rheumatology.

The risk of developing long COVID after infection with the Omicron variant appeared to be higher in patients with iRD, with 21% meeting the criteria set by the World Health Organization, compared with 13% of healthy individuals (odds ratio, 1.58; P = .037). Fatigue and loss of fitness were the most common long COVID symptoms reported by both iRD patients and controls. However, the difference in risk decreased after accounting for factors that are significantly associated with an increased risk for long COVID, such as body mass index and the severity of the acute COVID-19 infection (adjusted OR, 1.46; P = .081). The duration of symptoms did not show a statistically significant difference.

Kim Lauper, MD, University of Geneva, who chaired the session in which Ms. Boekel reported the study, said in an interview that the data should be interpreted with caution. “The data demonstrate that rheumatic disease itself is not a risk factor for long COVID. However, patients with rheumatic diseases are at a higher risk of severe disease, which in turn increases the likelihood of long COVID. Therefore, as a population, these patients are more susceptible to long COVID overall.”

Moreover, irrespective of their previous COVID-19 infection status, iRD patients often exhibit symptoms similar to those of long COVID even without a prior COVID-19 infection. (There was no history of COVID-19 in 21% of iRD patients vs. 11% of controls.) This suggests that some of the reported long COVID symptoms may actually be clinical manifestations of the underlying rheumatic disease, thereby complicating the diagnosis of long COVID in this population. The study employed the WHO definition of long COVID, which includes persistent symptoms lasting at least 8 weeks, beginning within 3 months of a confirmed SARS-CoV-2 infection, and that cannot be attributed to an alternative diagnosis. However, the data presented in Milan indicate that the WHO definition “is not well suited for patients with iRD due to significant overlap in symptoms and features,” Ms. Boekel concluded.

The cases of Omicron COVID-19 were identified during Jan. 1–April 25, 2022, among iRD patients recruited from the Amsterdam Rheumatology and Immunology Center. The population with confirmed SARS-CoV-2 Omicron infection during this period was monitored for long COVID. The total number of patients included in the study consisted of 77 iRD patients and 23 healthy controls. When asked about the potential risk of selection bias in the survey, Ms. Boekel stated that only approximately 8% of participants declined to respond, and the nonresponders were comparable with the respondents. She concluded that “the risk of selection bias is minimal.”

In an editorial published in The Lancet Rheumatology, Leonard H. Calabrese, DO, Cleveland Clinic, provided his insights on the findings. He emphasized that, “at present, long COVID remains an important reality that significantly impacts the lives of millions of individuals, yet it remains incompletely defined. ... These limitations in defining cases should not in any way undermine the experiences of those suffering from long COVID. Instead, they should serve as a reminder that, at this stage of the pandemic, we unfortunately still lack validated classification criteria for long COVID. It is crucial to include non–SARS-CoV-2–infected controls in all studies to further enhance our understanding.”

Ms. Boekel and coauthors, as well as Dr. Lauper and Dr. Calabrese, reported no relevant financial relationships.

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

MILAN – Rheumatic disease is not considered a significant risk factor for long COVID, according to the findings of a Dutch prospective cohort study presented at the annual European Congress of Rheumatology.

Although more patients with inflammatory rheumatic diseases (iRD) report symptoms resembling long COVID, the data suggest that many of these symptoms can be attributed to the underlying rheumatic disease. “Overall, we find the data quite reassuring,” said Laura Boekel, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center.

The results were also published in The Lancet Rheumatology.

The risk of developing long COVID after infection with the Omicron variant appeared to be higher in patients with iRD, with 21% meeting the criteria set by the World Health Organization, compared with 13% of healthy individuals (odds ratio, 1.58; P = .037). Fatigue and loss of fitness were the most common long COVID symptoms reported by both iRD patients and controls. However, the difference in risk decreased after accounting for factors that are significantly associated with an increased risk for long COVID, such as body mass index and the severity of the acute COVID-19 infection (adjusted OR, 1.46; P = .081). The duration of symptoms did not show a statistically significant difference.

Kim Lauper, MD, University of Geneva, who chaired the session in which Ms. Boekel reported the study, said in an interview that the data should be interpreted with caution. “The data demonstrate that rheumatic disease itself is not a risk factor for long COVID. However, patients with rheumatic diseases are at a higher risk of severe disease, which in turn increases the likelihood of long COVID. Therefore, as a population, these patients are more susceptible to long COVID overall.”

Moreover, irrespective of their previous COVID-19 infection status, iRD patients often exhibit symptoms similar to those of long COVID even without a prior COVID-19 infection. (There was no history of COVID-19 in 21% of iRD patients vs. 11% of controls.) This suggests that some of the reported long COVID symptoms may actually be clinical manifestations of the underlying rheumatic disease, thereby complicating the diagnosis of long COVID in this population. The study employed the WHO definition of long COVID, which includes persistent symptoms lasting at least 8 weeks, beginning within 3 months of a confirmed SARS-CoV-2 infection, and that cannot be attributed to an alternative diagnosis. However, the data presented in Milan indicate that the WHO definition “is not well suited for patients with iRD due to significant overlap in symptoms and features,” Ms. Boekel concluded.

The cases of Omicron COVID-19 were identified during Jan. 1–April 25, 2022, among iRD patients recruited from the Amsterdam Rheumatology and Immunology Center. The population with confirmed SARS-CoV-2 Omicron infection during this period was monitored for long COVID. The total number of patients included in the study consisted of 77 iRD patients and 23 healthy controls. When asked about the potential risk of selection bias in the survey, Ms. Boekel stated that only approximately 8% of participants declined to respond, and the nonresponders were comparable with the respondents. She concluded that “the risk of selection bias is minimal.”

In an editorial published in The Lancet Rheumatology, Leonard H. Calabrese, DO, Cleveland Clinic, provided his insights on the findings. He emphasized that, “at present, long COVID remains an important reality that significantly impacts the lives of millions of individuals, yet it remains incompletely defined. ... These limitations in defining cases should not in any way undermine the experiences of those suffering from long COVID. Instead, they should serve as a reminder that, at this stage of the pandemic, we unfortunately still lack validated classification criteria for long COVID. It is crucial to include non–SARS-CoV-2–infected controls in all studies to further enhance our understanding.”

Ms. Boekel and coauthors, as well as Dr. Lauper and Dr. Calabrese, reported no relevant financial relationships.

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

The ways in which artificial intelligence (AI) may transform the future of medicine is making headlines across the globe. But chances are, you’re already using AI in your practice every day – you may just not realize it.
 

And whether you recognize the presence of AI or not, the technology could be putting you in danger of a lawsuit, legal experts say.

The use of AI in your daily practice can come with hidden liabilities, say legal experts, and as hospitals and medical groups deploy AI into more areas of health care, new liability exposures may be on the horizon.

“For physicians, AI has also not yet drastically changed or improved the way care is provided or consumed,” said Michael LeTang, chief nursing informatics officer and vice president of risk management and patient safety at Healthcare Risk Advisors, part of TDC Group. “Consequently, it may seem like AI is not present in their work streams, but in reality, it has been utilized in health care for several years. As AI technologies continue to develop and become more sophisticated, we can expect them to play an increasingly significant role in health care.”

Today, most AI applications in health care use narrow AI, which is designed to complete a single task without human assistance, as opposed to artificial general intelligence (AGI), which pertains to human-level reasoning and problem solving across a broad spectrum. Here are some ways doctors are using AI throughout the day – sometimes being aware of its assistance, and sometimes being unaware:

• Many doctors use electronic health records (EHRs) with integrated AI that include computerized clinical decision support tools designed to reduce the risk of diagnostic error and to integrate decision-making in the medication ordering function.
• Cardiologists, pathologists, and dermatologists use AI in the interpretation of vast amounts of images, tracings, and complex patterns.
• Surgeons are using AI-enhanced surgical robotics for orthopedic surgeries, such as joint replacement and spine surgery.
• A growing number of doctors are using ChatGPT to assist in drafting prior authorization letters for insurers. Experts say more doctors are also experimenting with ChatGPT to support medical decision-making.
• Within oncology, physicians use machine learning techniques in the form of computer-aided detection systems for early breast cancer detection.
• AI algorithms are often used by health systems for workflow, staffing optimization, population management, and care coordination.
• Some systems within EHRs use AI to indicate high-risk patients.
• Physicians are using AI applications for the early recognition of sepsis, including EHR-integrated decision tools, such as the Hospital Corporation of America Healthcare’s Sepsis Prediction and Optimization Therapy and the Sepsis Early Risk Assessment algorithm.
• About 30% of radiologists use AI in their practice to analyze x-rays and CT scans.
• Epic Systems recently announced a partnership with Microsoft to integrate ChatGPT into MyChart, Epic’s patient portal system. Pilot hospitals will utilize ChatGPT to automatically generate responses to patient-generated questions sent via the portal.

The growth of AI in health care has been enormous, and it’s only going to continue, said Ravi B. Parikh, MD, an assistant professor in the department of medical ethics and health policy and medicine at the University of Pennsylvania, Philadelphia.

“What’s really critical is that physicians, clinicians, and nurses using AI are provided with the tools to understand how artificial intelligence works and, most importantly, understand that they are still accountable for making the ultimate decision,” Mr. LeTang said, “The information is not always going to be the right thing to do or the most accurate thing to do. They’re still liable for making a bad decision, even if AI is driving that.”
 

What are the top AI legal dangers of today?

A pressing legal risk is becoming too reliant on the suggestions that AI-based systems provide, which can lead to poor care decisions, said Kenneth Rashbaum, a New York–based cybersecurity attorney with more than 25 years of experience in medical malpractice defense.

This can occur, for example, when using clinical support systems that leverage AI, machine learning, or statistical pattern recognition. Today, clinical support systems are commonly administered through EHRs and other computerized clinical workflows. In general, such systems match a patient’s characteristics to a computerized clinical knowledge base. An assessment or recommendation is then presented to the physician for a decision.

“If the clinician blindly accepts it without considering whether it’s appropriate for this patient at this time with this presentation, the clinician may bear some responsibility if there is an untoward result,” Mr. Rashbaum said.

“A common claim even in the days before the EMR [electronic medical record] and AI, was that the clinician did not take all available information into account in rendering treatment, including history of past and present condition, as reflected in the records, communication with past and other present treating clinicians, lab and radiology results, discussions with the patient, and physical examination findings,” he said. “So, if the clinician relied upon the support prompt to the exclusion of these other sources of information, that could be a very strong argument for the plaintiff.”

Chatbots, such OpenAI’s ChatGPT, are another form of AI raising legal red flags. ChatGPT, trained on a massive set of text data, can carry out conversations, write code, draft emails, and answer any question posed. The chatbot has gained considerable credibility for accurately diagnosing rare conditions in seconds, and it recently passed the U.S. Medical Licensing Examination.

It’s unclear how many doctors are signing onto the ChatGPT website daily, but physicians are actively using the chatbot, particularly for assistance with prior authorization letters and to support decision-making processes in their practices, said Mr. LeTang.

When physicians ask ChatGPT a question, however, they should be mindful that ChatGPT could “hallucinate,” a term that refers to a generated response that sounds plausible but is factually incorrect or is unrelated to the context, explains Harvey Castro, MD, an emergency physician, ChatGPT health care expert, and author of the 2023 book “ChatGPT and Healthcare: Unlocking the Potential of Patient Empowerment.”

Acting on ChatGPT’s response without vetting the information places doctors at serious risk of a lawsuit, he said.

“Sometimes, the response is half true and half false,” he said. “Say, I go outside my specialty of emergency medicine and ask it about a pediatric surgical procedure. It could give me a response that sounds medically correct, but then I ask a pediatric cardiologist, and he says, ‘We don’t even do this. This doesn’t even exist!’ Physicians really have to make sure they are vetting the information provided.”

In response to ChatGPT’s growing usage by health care professionals, hospitals and practices are quickly implementing guidelines, policies, and restrictions that caution physicians about the accuracy of ChatGPT-generated information, adds Mr. LeTang.

Emerging best practices include avoiding the input of patient health information, personally identifiable information, or any data that could be commercially valuable or considered the intellectual property of a hospital or health system, he said.

“Another crucial guideline is not to rely solely on ChatGPT as a definitive source for clinical decision-making; physicians must exercise their professional judgment,” he said. “If best practices are not adhered to, the associated risks are present today. However, these risks may become more significant as AI technologies continue to evolve and become increasingly integrated into health care.”

The potential for misdiagnosis by AI systems and the risk of unnecessary procedures if physicians do not thoroughly evaluate and validate AI predictions are other dangers.

As an example, Mr. LeTang described a case in which a physician documents in the EHR that a patient has presented to the emergency department with chest pains and other signs of a heart attack, and an AI algorithm predicts that the patient is experiencing an active myocardial infarction. If the physician then sends the patient for stenting or an angioplasty without other concrete evidence or tests to confirm the diagnosis, the doctor could later face a misdiagnosis complaint if the costly procedures were unnecessary.

“That’s one of the risks of using artificial intelligence,” he said. “A large percentage of malpractice claims is failure to diagnose, delayed diagnosis, or inaccurate diagnosis. What falls in the category of failure to diagnose is sending a patient for an unnecessary procedure or having an adverse event or bad outcome because of the failure to diagnose.”

So far, no AI lawsuits have been filed, but they may make an appearance soon, said Sue Boisvert, senior patient safety risk manager at The Doctors Company, a national medical liability insurer.

“There are hundreds of AI programs currently in use in health care,” she said. “At some point, a provider will make a decision that is contrary to what the AI recommended. The AI may be wrong, or the provider may be wrong. Either way, the provider will neglect to document their clinical reasoning, a patient will be harmed, and we will have the first AI claim.”
 

Upcoming AI legal risks to watch for

Lawsuits that allege biased patient care by physicians on the basis of algorithmic bias may also be forthcoming, analysts warn.

Much has been written about algorithmic bias that compounds and worsens inequities in socioeconomic status, ethnicity, sexual orientation, and gender in health systems. In 2019, a groundbreaking article in Science shed light on commonly used algorithms that are considered racially biased and how health care professionals often use such information to make medical decisions.

No claims involving AI bias have come down the pipeline yet, but it’s an area to watch, said Ms. Boisvert. She noted a website that highlights complaints and accusations of AI bias, including in health care.

“We need to be sure the training of the AI is appropriate, current, and broad enough so that there is no bias in the AI when it’s participating in the decision-making,” said Ms. Boisvert. “Imagine if the AI is diagnosing based on a dataset that is not local. It doesn’t represent the population at that particular hospital, and it’s providing inaccurate information to the physicians who are then making decisions about treatment.”

In pain management, for example, there are known differences in how patients experience pain, Ms. Boisvert said. If AI was being used to develop an algorithm for how a particular patient’s postoperative pain should be managed, and the algorithm did not include the differences, the pain control for a certain patient could be inappropriate. A poor outcome resulting from the treatment could lead to a claim against the physician or hospital that used the biased AI system, she said.

In the future, as AI becomes more integrated and accepted in medicine, there may be a risk of legal complaints against doctors for not using AI, said Saurabh Jha, MD, an associate professor of radiology at the University of Pennsylvania, Philadelphia, and a scholar of AI in radiology.

“Ultimately, we might get to a place where AI starts helping physicians detect more or reduce the miss of certain conditions, and it becomes the standard of care,” Dr. Jha said. “For example, if it became part of the standard of care for pulmonary embolism [PE] detection, and you didn’t use it for PE detection, and there was a miss. That could put you at legal risk. We’re not at that stage yet, but that is one future possibility.”

Dr. Parikh envisions an even cloudier liability landscape as the potential grows for AI to control patient care decisions. In such a scenario, rather than just issuing an alert or prediction to a physician, the AI system could trigger an action.

For instance, if an algorithm is trained to predict sepsis and, once triggered, the AI could initiate a nurse-led rapid response or a change in patient care outside the clinician’s control, said Dr. Parikh, who coauthored a recent article on AI and medical liability in The Milbank Quarterly.

“That’s still very much the minority of how AI is being used, but as evidence is growing that AI-based diagnostic tools perform equivalent or even superior to physicians, these autonomous workflows are being considered,” Dr. Parikh said. “When the ultimate action upon the patient is more determined by the AI than what the clinician does, then I think the liability picture gets murkier, and we should be thinking about how we can respond to that from a liability framework.”
 

How you can prevent AI-related lawsuits

The first step to preventing an AI-related claim is being aware of when and how you are using AI.

Ensure you’re informed about how the AI was trained, Ms. Boisvert stresses.

“Ask questions!” she said. “Is the AI safe? Are the recommendations accurate? Does the AI perform better than current systems? In what way? What databases were used, and did the programmers consider bias? Do I understand how to use the results?”

Never blindly trust the AI but rather view it as a data point in a medical decision, said Dr. Parikh. Ensure that other sources of medical information are properly accessed and that best practices for your specialty are still being followed.

When using any form of AI, document your usage, adds Mr. Rashbaum. A record that clearly outlines how the physician incorporated the AI is critical if a claim later arises in which the doctor is accused of AI-related malpractice, he said.

“Indicating how the AI tool was used, why it was used, and that it was used in conjunction with available clinical information and the clinician’s best judgment could reduce the risk of being found responsible as a result of AI use in a particular case,” he said.

Use chatbots, such as ChatGPT, the way they were intended, as support tools, rather than definitive diagnostic instruments, adds Dr. Castro.

“Doctors should also be well-trained in interpreting and understanding the suggestions provided by ChatGPT and should use their clinical judgment and experience alongside the AI tool for more accurate decision-making,” he said.

In addition, because no AI insurance product exists on the market, physicians and organizations using AI – particularly for direct health care – should evaluate their current insurance or insurance-like products to determine where a claim involving AI might fall and whether the policy would respond, said Ms. Boisvert. The AI vendor/manufacturer will likely have indemnified themselves in the purchase and sale agreement or contract, she said.

It will also become increasingly important for medical practices, hospitals, and health systems to put in place strong data governance strategies, Mr. LeTang said.

“AI relies on good data,” he said. “A data governance strategy is a key component to making sure we understand where the data is coming from, what is represents, how accurate it is, if it’s reproducible, what controls are in place to ensure the right people have the right access, and that if we’re starting to use it to build algorithms, that it’s deidentified.”

While no malpractice claims associated with the use of AI have yet surfaced, this may change as legal courts catch up on the backlog of malpractice claims that were delayed because of COVID-19, and even more so as AI becomes more prevalent in health care, Mr. LeTang said.

“Similar to the attention that autonomous driving systems, like Tesla, receive when the system fails and accidents occur, we can be assured that media outlets will widely publicize AI-related medical adverse events,” he said. “It is crucial for health care professionals, AI developers, and regulatory authorities to work together to ensure the responsible use of AI in health care, with patient safety as the top priority. By doing so, they can mitigate the risks associated with AI implementation and minimize the potential for legal disputes arising from AI-related medical errors.”

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