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RA and demyelinating disease: No consistent link to TNFi
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
High-intensity interval training has sustainable effects in patients with inflammatory arthritis
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.
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 (VO2 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 VO2 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 VO2 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 VO2 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.
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 (VO2 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 VO2 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 VO2 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 VO2 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.
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 (VO2 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 VO2 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 VO2 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 VO2 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.
AT EULAR 2023
Why not both? Dual biologics for treatment-resistant RA and PsA
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.
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.
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.
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.
Is ChatGPT a friend or foe of medical publishing?
. 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.
. 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.
. 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.
Studies reveal nuances in efficacy, MACE risk between JAKi and TNFi
Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.
Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD
The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.
Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.
The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.
Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.
Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
A real-world perspective
MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.
Mr. Aymon said that the analysis is still ongoing, with additional registries being included.
Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
The Dutch perspective
In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.
“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.
“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.
Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.
Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD
The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.
Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.
The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.
Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.
Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
A real-world perspective
MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.
Mr. Aymon said that the analysis is still ongoing, with additional registries being included.
Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
The Dutch perspective
In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.
“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.
“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.
Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.
Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD
The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.
Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.
The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.
Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.
Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
A real-world perspective
MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.
Mr. Aymon said that the analysis is still ongoing, with additional registries being included.
Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
The Dutch perspective
In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.
“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.
“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.
Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
ILD risk elevated in RA, PsA after starting biologic or targeted synthetic DMARDs
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
AT EULAR 2023
Commentary: Ongoing therapy options in RA, June 2023
Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.
Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.
Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.
Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.
Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.
Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.
Several environmental risk factors are associated with the development of rheumatoid arthritis (RA), with smoking having one of the strongest associations. Exposure to airborne toxins has also been associated with development of anti–cyclic citrullinated peptide antibodies. Beidelschies and colleagues performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey to examine a potential interaction between smoking and polycyclic aromatic hydrocarbons (PAH) affecting the development of RA. Stored blood and urine samples of survey respondents were examined, and levels of PAH as well as other toxicants were measured. Of nearly 22,000 participants, about 1400 of whom reported a diagnosis of RA, toxicants were measured in about 7000. Higher levels of PAH and phthalate metabolites were more strongly associated with development of RA. Because cigarettes are a source of PAH, the authors postulated that PAH mediated the impact of smoking on development of RA, a plausible explanation given that smoking was not associated with RA after adjustment for PAH levels. However, given the cross-sectional design, causality cannot be determined.
Janus kinase (JAK) inhibitors have been found in several surveillance studies to be associated with an increased risk for cancer and cardiovascular events. Westermann and colleagues performed an observational cohort study using Danish nationwide registries to evaluate cancer risk (other than nonmelanomatous skin cancer) in patients with RA treated with tofacitinib or baricitinib. Among 875 patients treated with JAK inhibitors vs 4247 patients treated with biologic disease-modifying antirheumatic drugs (bDMARD), cancer incidence rates were similar (14.4 vs 12.9 per 1000 patient-years, respectively). Interestingly, though cancer incidence rates increased in patients > 50 and those > 65 years of age, the effect was similar between patients treated with JAK inhibitors and bDMARD. The largest difference was seen in patients up to 1 year vs > 1 year of follow-up, with hazard ratios of 1.54 vs 1.07. These findings are somewhat reassuring in light of results from the ORAL Surveillance study, suggesting increased cancer and cardiovascular risk among older patients with RA. However, as with bDMARD, increased scrutiny may be warranted among patients > 65 years, especially in the first year of treatment.
Finally, regarding withdrawal of therapy, Curtis and colleagues performed a randomized controlled study of patients with RA on combination therapy with methotrexate and etanercept and evaluated factors associated with maintenance of remission. In this study, withdrawal of methotrexate and etanercept were compared: About 250 patients whose disease was in remission, on the basis of the Simplified Disease Activity Index, were randomized in a 2:2:1 ratio to receive methotrexate monotherapy, etanercept monotherapy, or combination therapy. Prior analyses of these data have shown that continuing etanercept monotherapy showed a benefit in maintaining remission compared with continuing methotrexate monotherapy. Several baseline characteristics, including higher patient global activity at baseline and rheumatoid factor seropositivity, were associated with a lower likelihood of maintaining remission or low disease activity. Interestingly, higher serum magnesium levels seemed to negatively affect maintenance of remission, though the mechanism for this finding is not clear. In general, however, this study did not add more information to prior work in terms of shedding light on which patients may be able to stop therapy.
FDA approves Yuflyma as ninth adalimumab biosimilar
The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.
The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”
The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.
“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.
The citrate-free formulation is thought to lead to less pain on injection.
Yuflyma will be available in prefilled syringe and autoinjector administration options.
Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.
Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.
If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.
Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.
In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.
In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.
The full prescribing information for Yuflyma is available here.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.
The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”
The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.
“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.
The citrate-free formulation is thought to lead to less pain on injection.
Yuflyma will be available in prefilled syringe and autoinjector administration options.
Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.
Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.
If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.
Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.
In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.
In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.
The full prescribing information for Yuflyma is available here.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.
The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”
The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.
“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.
The citrate-free formulation is thought to lead to less pain on injection.
Yuflyma will be available in prefilled syringe and autoinjector administration options.
Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.
Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.
If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.
Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.
In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.
In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.
The full prescribing information for Yuflyma is available here.
A version of this article first appeared on Medscape.com.
FDA approves autoinjector pen for Humira biosimilar, Cyltezo
The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.
Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.
“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.
Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.
“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.
Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.
“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”
A version of this article first appeared on Medscape.com.
Worse outcomes among elderly patients with RA undergoing percutaneous coronary intervention
Key clinical point: The risk for all-cause mortality is higher among elderly patients with vs without rheumatoid arthritis (RA) who undergo percutaneous coronary intervention (PCI), with the risk being the highest among those with elderly-onset RA (disease presentation after 65 years of age).
Major finding: During the 10-year follow-up, all-cause mortality-associated survival rates were significantly lower in patients with vs without RA (53.7% vs 58.3%; log-rank P < .001) and in patients with elderly-onset vs young-onset RA (48.1% vs 73.7%; log-rank P < .001). Trends were similar for cardiovascular disease-associated survival rates (all log-rank P < .001).
Study details: This was a population-based retrospective cohort study including 74,623 patients age ≥ 65 years with (n = 14,074) or without (n = 60,549) RA who were diagnosed with acute coronary syndrome and underwent PCI.
Disclosures: This study was funded by Soonchunhyang University, South Korea, and the Asan Foundation, South Korea. The authors declared no conflicts of interest.
Source: Kim BY et al. Outcomes of percutaneous coronary intervention in elderly patients with rheumatoid arthritis: A nationwide population-based cohort study. Healthcare (Basel). 2023;11(10):1381 (May 10). Doi: 10.3390/healthcare11101381
Key clinical point: The risk for all-cause mortality is higher among elderly patients with vs without rheumatoid arthritis (RA) who undergo percutaneous coronary intervention (PCI), with the risk being the highest among those with elderly-onset RA (disease presentation after 65 years of age).
Major finding: During the 10-year follow-up, all-cause mortality-associated survival rates were significantly lower in patients with vs without RA (53.7% vs 58.3%; log-rank P < .001) and in patients with elderly-onset vs young-onset RA (48.1% vs 73.7%; log-rank P < .001). Trends were similar for cardiovascular disease-associated survival rates (all log-rank P < .001).
Study details: This was a population-based retrospective cohort study including 74,623 patients age ≥ 65 years with (n = 14,074) or without (n = 60,549) RA who were diagnosed with acute coronary syndrome and underwent PCI.
Disclosures: This study was funded by Soonchunhyang University, South Korea, and the Asan Foundation, South Korea. The authors declared no conflicts of interest.
Source: Kim BY et al. Outcomes of percutaneous coronary intervention in elderly patients with rheumatoid arthritis: A nationwide population-based cohort study. Healthcare (Basel). 2023;11(10):1381 (May 10). Doi: 10.3390/healthcare11101381
Key clinical point: The risk for all-cause mortality is higher among elderly patients with vs without rheumatoid arthritis (RA) who undergo percutaneous coronary intervention (PCI), with the risk being the highest among those with elderly-onset RA (disease presentation after 65 years of age).
Major finding: During the 10-year follow-up, all-cause mortality-associated survival rates were significantly lower in patients with vs without RA (53.7% vs 58.3%; log-rank P < .001) and in patients with elderly-onset vs young-onset RA (48.1% vs 73.7%; log-rank P < .001). Trends were similar for cardiovascular disease-associated survival rates (all log-rank P < .001).
Study details: This was a population-based retrospective cohort study including 74,623 patients age ≥ 65 years with (n = 14,074) or without (n = 60,549) RA who were diagnosed with acute coronary syndrome and underwent PCI.
Disclosures: This study was funded by Soonchunhyang University, South Korea, and the Asan Foundation, South Korea. The authors declared no conflicts of interest.
Source: Kim BY et al. Outcomes of percutaneous coronary intervention in elderly patients with rheumatoid arthritis: A nationwide population-based cohort study. Healthcare (Basel). 2023;11(10):1381 (May 10). Doi: 10.3390/healthcare11101381