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Skip Potassium After Cardiac Surgery
LONDON —
“The widespread practice of giving patients potassium after bypass heart surgery even though their blood levels are within the normal range can be abandoned,” said Benjamin O’Brien, MD, PhD, director of the Clinic for Cardioanesthesiology and Intensive Care Medicine at Charité Hospital in Berlin, Germany.
Results from the randomized TIGHT-K trial that assessed two levels of potassium supplementation were presented at the annual congress of the European Society of Cardiology.
In the tight-control group, supplementation was provided to maintain high-normal levels of potassium (> 4.5 mEq/L). In the relaxed-control group, supplementation was provided only when potassium levels fell below the low-normal threshold (< 3.6 mEq/L).
Trial Upending Popular Practice
The multinational trial involved 23 centers in Germany and the United Kingdom. All 1690 participants enrolled were scheduled to undergo a coronary artery bypass graft procedure, but Dr. O’Brien said he considers the results of TIGHT-K to be broadly applicable.
“There is no physiological basis to expect a different result in patients undergoing different types of cardiac surgery,” he said.
The primary endpoint was clinically and electrocardiography confirmed new-onset atrial fibrillation that occurred in the 5 days after the bypass procedure.
For the primary atrial fibrillation endpoint, event rates were similar in the tight-control and the relaxed-control groups (26.2% vs 27.8%); the 1.7% difference did not approach statistical significance (P = .44). The difference in dysrhythmias other than atrial fibrillation, although numerically lower in the tight-control group, was also not significant (19.1% vs 21.1%; P = .26).
There were no significant differences in several secondary endpoints, including length of hospital stay and in-patient mortality, but cost, a prespecified secondary endpoint, was approximately $120 lower per patient in the relaxed-control group than in the tight-control group (P < .001).
Lowering Cost Across Cardiac Surgeries
During the 5-day follow-up, median potassium levels were higher in the tight-control group. Levels in both groups fell gradually, but essentially in parallel, over the study period, so median potassium levels were always higher in the tight-control group than in the relaxed-control group. At the end of the observation period, mean potassium levels were 4.34 mEq/L in the tight-control group and 4.08 mEq/L in the relaxed-control group.
Prior to the development of atrial fibrillation, participants in the tight-control group received a medium of seven potassium administrations (range, 4-12), whereas those in the relaxed-control group received a medium of zero.
There were no significant differences in episodes in any subgroup evaluated, including those divided by age, sex, baseline left ventricular ejection fraction, and the absence or presence of beta blockers or loop diuretics. A per-protocol analysis also failed to show any advantage for tight potassium control.
Atrial fibrillation occurs in about one third of patients after bypass surgery, as it does after many types of cardiac surgery. Institutions often have strategies in place to reduce the risk after cardiac surgery, and potassium supplementation is one of the most common, despite the lack of supportive evidence, Dr. O’Brien said.
Narrow Window for Optimal Potassium Levels
The difference in potassium levels between the tight-control group and the relaxed-control group were modest in this study, said Subodh Verma, MD, a cardiac surgeon at St Michael’s Hospital and professor at the University of Toronto, Ontario, Canada.
However, this is unavoidable and central to the question being posed, Dr. O’Brien pointed out. Because of the risks for both hypokalemia and hyperkalemia, the window for safe supplementation is short. Current practice is to achieve high-normal levels to reduce atrial fibrillation, but TIGHT-K demonstrates this has no benefit.
The conclusion of TIGHT-K is appropriate, said Faiez Zannad, MD, PhD, professor of therapeutics in the Division of Cardiology at the University of Lorraine in Nancy, France, who praised the design and conduct of the study.
He acknowledged an unmet need for effective methods to reduce the risk for atrial fibrillation after cardiac surgery, but the ESC invited discussant said it is now necessary to look at other strategies. Several are under current evaluation, such as supplementary magnesium and the use of sodium-glucose transporter-2 inhibitors.
Although Dr. Zannad encouraged more studies of methods to reduce atrial fibrillation risk after cardiac surgery, he said that TIGHT-K has answered the question of whether potassium supplementation is beneficial.
Potassium supplementation should no longer be offered, he said, which will “reduce healthcare costs and decrease patient risk from an unnecessary intervention.”
A version of this article first appeared on Medscape.com.
LONDON —
“The widespread practice of giving patients potassium after bypass heart surgery even though their blood levels are within the normal range can be abandoned,” said Benjamin O’Brien, MD, PhD, director of the Clinic for Cardioanesthesiology and Intensive Care Medicine at Charité Hospital in Berlin, Germany.
Results from the randomized TIGHT-K trial that assessed two levels of potassium supplementation were presented at the annual congress of the European Society of Cardiology.
In the tight-control group, supplementation was provided to maintain high-normal levels of potassium (> 4.5 mEq/L). In the relaxed-control group, supplementation was provided only when potassium levels fell below the low-normal threshold (< 3.6 mEq/L).
Trial Upending Popular Practice
The multinational trial involved 23 centers in Germany and the United Kingdom. All 1690 participants enrolled were scheduled to undergo a coronary artery bypass graft procedure, but Dr. O’Brien said he considers the results of TIGHT-K to be broadly applicable.
“There is no physiological basis to expect a different result in patients undergoing different types of cardiac surgery,” he said.
The primary endpoint was clinically and electrocardiography confirmed new-onset atrial fibrillation that occurred in the 5 days after the bypass procedure.
For the primary atrial fibrillation endpoint, event rates were similar in the tight-control and the relaxed-control groups (26.2% vs 27.8%); the 1.7% difference did not approach statistical significance (P = .44). The difference in dysrhythmias other than atrial fibrillation, although numerically lower in the tight-control group, was also not significant (19.1% vs 21.1%; P = .26).
There were no significant differences in several secondary endpoints, including length of hospital stay and in-patient mortality, but cost, a prespecified secondary endpoint, was approximately $120 lower per patient in the relaxed-control group than in the tight-control group (P < .001).
Lowering Cost Across Cardiac Surgeries
During the 5-day follow-up, median potassium levels were higher in the tight-control group. Levels in both groups fell gradually, but essentially in parallel, over the study period, so median potassium levels were always higher in the tight-control group than in the relaxed-control group. At the end of the observation period, mean potassium levels were 4.34 mEq/L in the tight-control group and 4.08 mEq/L in the relaxed-control group.
Prior to the development of atrial fibrillation, participants in the tight-control group received a medium of seven potassium administrations (range, 4-12), whereas those in the relaxed-control group received a medium of zero.
There were no significant differences in episodes in any subgroup evaluated, including those divided by age, sex, baseline left ventricular ejection fraction, and the absence or presence of beta blockers or loop diuretics. A per-protocol analysis also failed to show any advantage for tight potassium control.
Atrial fibrillation occurs in about one third of patients after bypass surgery, as it does after many types of cardiac surgery. Institutions often have strategies in place to reduce the risk after cardiac surgery, and potassium supplementation is one of the most common, despite the lack of supportive evidence, Dr. O’Brien said.
Narrow Window for Optimal Potassium Levels
The difference in potassium levels between the tight-control group and the relaxed-control group were modest in this study, said Subodh Verma, MD, a cardiac surgeon at St Michael’s Hospital and professor at the University of Toronto, Ontario, Canada.
However, this is unavoidable and central to the question being posed, Dr. O’Brien pointed out. Because of the risks for both hypokalemia and hyperkalemia, the window for safe supplementation is short. Current practice is to achieve high-normal levels to reduce atrial fibrillation, but TIGHT-K demonstrates this has no benefit.
The conclusion of TIGHT-K is appropriate, said Faiez Zannad, MD, PhD, professor of therapeutics in the Division of Cardiology at the University of Lorraine in Nancy, France, who praised the design and conduct of the study.
He acknowledged an unmet need for effective methods to reduce the risk for atrial fibrillation after cardiac surgery, but the ESC invited discussant said it is now necessary to look at other strategies. Several are under current evaluation, such as supplementary magnesium and the use of sodium-glucose transporter-2 inhibitors.
Although Dr. Zannad encouraged more studies of methods to reduce atrial fibrillation risk after cardiac surgery, he said that TIGHT-K has answered the question of whether potassium supplementation is beneficial.
Potassium supplementation should no longer be offered, he said, which will “reduce healthcare costs and decrease patient risk from an unnecessary intervention.”
A version of this article first appeared on Medscape.com.
LONDON —
“The widespread practice of giving patients potassium after bypass heart surgery even though their blood levels are within the normal range can be abandoned,” said Benjamin O’Brien, MD, PhD, director of the Clinic for Cardioanesthesiology and Intensive Care Medicine at Charité Hospital in Berlin, Germany.
Results from the randomized TIGHT-K trial that assessed two levels of potassium supplementation were presented at the annual congress of the European Society of Cardiology.
In the tight-control group, supplementation was provided to maintain high-normal levels of potassium (> 4.5 mEq/L). In the relaxed-control group, supplementation was provided only when potassium levels fell below the low-normal threshold (< 3.6 mEq/L).
Trial Upending Popular Practice
The multinational trial involved 23 centers in Germany and the United Kingdom. All 1690 participants enrolled were scheduled to undergo a coronary artery bypass graft procedure, but Dr. O’Brien said he considers the results of TIGHT-K to be broadly applicable.
“There is no physiological basis to expect a different result in patients undergoing different types of cardiac surgery,” he said.
The primary endpoint was clinically and electrocardiography confirmed new-onset atrial fibrillation that occurred in the 5 days after the bypass procedure.
For the primary atrial fibrillation endpoint, event rates were similar in the tight-control and the relaxed-control groups (26.2% vs 27.8%); the 1.7% difference did not approach statistical significance (P = .44). The difference in dysrhythmias other than atrial fibrillation, although numerically lower in the tight-control group, was also not significant (19.1% vs 21.1%; P = .26).
There were no significant differences in several secondary endpoints, including length of hospital stay and in-patient mortality, but cost, a prespecified secondary endpoint, was approximately $120 lower per patient in the relaxed-control group than in the tight-control group (P < .001).
Lowering Cost Across Cardiac Surgeries
During the 5-day follow-up, median potassium levels were higher in the tight-control group. Levels in both groups fell gradually, but essentially in parallel, over the study period, so median potassium levels were always higher in the tight-control group than in the relaxed-control group. At the end of the observation period, mean potassium levels were 4.34 mEq/L in the tight-control group and 4.08 mEq/L in the relaxed-control group.
Prior to the development of atrial fibrillation, participants in the tight-control group received a medium of seven potassium administrations (range, 4-12), whereas those in the relaxed-control group received a medium of zero.
There were no significant differences in episodes in any subgroup evaluated, including those divided by age, sex, baseline left ventricular ejection fraction, and the absence or presence of beta blockers or loop diuretics. A per-protocol analysis also failed to show any advantage for tight potassium control.
Atrial fibrillation occurs in about one third of patients after bypass surgery, as it does after many types of cardiac surgery. Institutions often have strategies in place to reduce the risk after cardiac surgery, and potassium supplementation is one of the most common, despite the lack of supportive evidence, Dr. O’Brien said.
Narrow Window for Optimal Potassium Levels
The difference in potassium levels between the tight-control group and the relaxed-control group were modest in this study, said Subodh Verma, MD, a cardiac surgeon at St Michael’s Hospital and professor at the University of Toronto, Ontario, Canada.
However, this is unavoidable and central to the question being posed, Dr. O’Brien pointed out. Because of the risks for both hypokalemia and hyperkalemia, the window for safe supplementation is short. Current practice is to achieve high-normal levels to reduce atrial fibrillation, but TIGHT-K demonstrates this has no benefit.
The conclusion of TIGHT-K is appropriate, said Faiez Zannad, MD, PhD, professor of therapeutics in the Division of Cardiology at the University of Lorraine in Nancy, France, who praised the design and conduct of the study.
He acknowledged an unmet need for effective methods to reduce the risk for atrial fibrillation after cardiac surgery, but the ESC invited discussant said it is now necessary to look at other strategies. Several are under current evaluation, such as supplementary magnesium and the use of sodium-glucose transporter-2 inhibitors.
Although Dr. Zannad encouraged more studies of methods to reduce atrial fibrillation risk after cardiac surgery, he said that TIGHT-K has answered the question of whether potassium supplementation is beneficial.
Potassium supplementation should no longer be offered, he said, which will “reduce healthcare costs and decrease patient risk from an unnecessary intervention.”
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2024
New AFib Guidelines Address Underlying Illness, Comorbidities
LONDON — Updated guidelines for the management of atrial fibrillation released by the European Society of Cardiology are revamping the approach to care for this complex, multifactorial disease.
, Isabelle Van Gelder, MD, PhD, professor of cardiology at the University Medical Center in Groningen, the Netherlands, explained at the European Society of Cardiology (ESC) Congress.
It is not just appropriate to place the same emphasis on the control of comorbidities as on the rhythm disturbance, it is critical, said Dr. Van Gelder, who served as chair of the ESC-AF guidelines task force.
Comorbidities are the drivers of both the onset and recurrence of atrial fibrillation, and a dynamic approach to comorbidities is “central for the success of AF management.”
Class I Recommendation
In fact, on the basis of overwhelming evidence, a class I recommendation has been issued for a large number of goals in the comorbidity and risk factor management step of atrial fibrillation management, including those for hypertension, components of heart failure, obesity, diabetes, alcohol consumption, and exercise.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors “should be offered to all patients with AF,” according to Dr. Van Gelder, who identified this as a new class I recommendation.
Patients who are not managed aggressively for the listed comorbidities ultimately face “treatment failure, poor patient outcomes, and a waste of healthcare resources,” she said.
Control of sleep apnea is also noted as a key target, although Van Gelder acknowledged that the supporting evidence only allows for a class IIb recommendation.
Control of comorbidities is not a new idea. In the 2023 joint guideline, led by a consortium of professional groups, including the American Heart Association (AHA) and the American College of Cardiology (ACC), the control of comorbidities, including most of those identified in the new ESC guidelines, was second in a list of 10 key take-home messages.
However, the new ESC guidelines have prioritized comorbidity management by listing it first in each of the specific patient-care pathways developed to define optimized care.
These pathways, defined in algorithms for newly diagnosed AF, paroxysmal AF, and persistent AF, always start with the assessment of comorbidities, followed by step A — avoiding stroke — largely with anticoagulation.
Direct oral anticoagulants should be used, “except in those with a mechanical valve or mitral stenosis,” Dr. Van Gelder said. This includes, essentially, all patients with a CHA2DS2-VASc score of 2 or greater, and it should be “considered” in those with a score of 1.
The ESC framework has been identified with the acronym AF-CARE, in which the C stands for comorbidities.
In the A step of the framework, identifying and treating all modifiable bleeding risk factors in AF patients is a class I recommendation. On the basis of a class III recommendation, she cautioned against withholding anticoagulants because of CHA2DS2-VASc risk factors alone. Rather, Dr. Van Gelder called the decision to administer or withhold anticoagulation — like all decisions — one that should be individualized in consultation with the patient.
For reducing AF symptoms and rhythm control, the specific pathways diverge for newly diagnosed AF, paroxysmal AF, and persistent AF. Like all of the guidelines, the specific options for symptom management and AF ablation are color coded, with green signifying level 1 evidence.
The evaluation and dynamic reassessment step refers to the need to periodically assess patients for new modifiable risk factors related to comorbidities, risk for stroke, risk for bleeding, and risk for AF.
The management of risk factors for AF has long been emphasized in guidelines, but a previous focus on AF with attention to comorbidities has been replaced by a focus on comorbidities with an expectation of more durable AF control. The success of this pivot is based on multidisciplinary care, chosen in collaboration with the patient, to reduce or eliminate the triggers of AF and the risks of its complications.
Pathways Are Appropriate for All Patients
A very important recommendation — and this is new — is “to treat all our patients with atrial fibrillation, whether they are young or old, men or women, Black or White, or at high or low risk, according to our patient-centered integrated AF-CARE approach,” Dr. Van Gelder said.
The changes reflect a shared appreciation for the tight relation between the control of comorbidities and the control of AF, according to José A. Joglar, MD, professor of cardiac electrophysiologic research at the University of Texas Southwestern Medical Center in Dallas. Dr. Joglar was chair of the writing committee for the joint 2023 AF guidelines released by the AHA, ACC, the American College of Clinical Pharmacy, and the Heart Rhythm Society.
“It is increasingly clear that AF in many cases is the consequence of underlying risk factors and comorbidities, which cannot be separated from AF alone,” Dr. Joglar explained in an interview.
This was placed first “to emphasize the importance of viewing AFib as a complex disease that requires a holistic, multidisciplinary approach to care, as opposed to being viewed just as a rhythm abnormality,” he said.
A version of this article first appeared on Medscape.com.
LONDON — Updated guidelines for the management of atrial fibrillation released by the European Society of Cardiology are revamping the approach to care for this complex, multifactorial disease.
, Isabelle Van Gelder, MD, PhD, professor of cardiology at the University Medical Center in Groningen, the Netherlands, explained at the European Society of Cardiology (ESC) Congress.
It is not just appropriate to place the same emphasis on the control of comorbidities as on the rhythm disturbance, it is critical, said Dr. Van Gelder, who served as chair of the ESC-AF guidelines task force.
Comorbidities are the drivers of both the onset and recurrence of atrial fibrillation, and a dynamic approach to comorbidities is “central for the success of AF management.”
Class I Recommendation
In fact, on the basis of overwhelming evidence, a class I recommendation has been issued for a large number of goals in the comorbidity and risk factor management step of atrial fibrillation management, including those for hypertension, components of heart failure, obesity, diabetes, alcohol consumption, and exercise.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors “should be offered to all patients with AF,” according to Dr. Van Gelder, who identified this as a new class I recommendation.
Patients who are not managed aggressively for the listed comorbidities ultimately face “treatment failure, poor patient outcomes, and a waste of healthcare resources,” she said.
Control of sleep apnea is also noted as a key target, although Van Gelder acknowledged that the supporting evidence only allows for a class IIb recommendation.
Control of comorbidities is not a new idea. In the 2023 joint guideline, led by a consortium of professional groups, including the American Heart Association (AHA) and the American College of Cardiology (ACC), the control of comorbidities, including most of those identified in the new ESC guidelines, was second in a list of 10 key take-home messages.
However, the new ESC guidelines have prioritized comorbidity management by listing it first in each of the specific patient-care pathways developed to define optimized care.
These pathways, defined in algorithms for newly diagnosed AF, paroxysmal AF, and persistent AF, always start with the assessment of comorbidities, followed by step A — avoiding stroke — largely with anticoagulation.
Direct oral anticoagulants should be used, “except in those with a mechanical valve or mitral stenosis,” Dr. Van Gelder said. This includes, essentially, all patients with a CHA2DS2-VASc score of 2 or greater, and it should be “considered” in those with a score of 1.
The ESC framework has been identified with the acronym AF-CARE, in which the C stands for comorbidities.
In the A step of the framework, identifying and treating all modifiable bleeding risk factors in AF patients is a class I recommendation. On the basis of a class III recommendation, she cautioned against withholding anticoagulants because of CHA2DS2-VASc risk factors alone. Rather, Dr. Van Gelder called the decision to administer or withhold anticoagulation — like all decisions — one that should be individualized in consultation with the patient.
For reducing AF symptoms and rhythm control, the specific pathways diverge for newly diagnosed AF, paroxysmal AF, and persistent AF. Like all of the guidelines, the specific options for symptom management and AF ablation are color coded, with green signifying level 1 evidence.
The evaluation and dynamic reassessment step refers to the need to periodically assess patients for new modifiable risk factors related to comorbidities, risk for stroke, risk for bleeding, and risk for AF.
The management of risk factors for AF has long been emphasized in guidelines, but a previous focus on AF with attention to comorbidities has been replaced by a focus on comorbidities with an expectation of more durable AF control. The success of this pivot is based on multidisciplinary care, chosen in collaboration with the patient, to reduce or eliminate the triggers of AF and the risks of its complications.
Pathways Are Appropriate for All Patients
A very important recommendation — and this is new — is “to treat all our patients with atrial fibrillation, whether they are young or old, men or women, Black or White, or at high or low risk, according to our patient-centered integrated AF-CARE approach,” Dr. Van Gelder said.
The changes reflect a shared appreciation for the tight relation between the control of comorbidities and the control of AF, according to José A. Joglar, MD, professor of cardiac electrophysiologic research at the University of Texas Southwestern Medical Center in Dallas. Dr. Joglar was chair of the writing committee for the joint 2023 AF guidelines released by the AHA, ACC, the American College of Clinical Pharmacy, and the Heart Rhythm Society.
“It is increasingly clear that AF in many cases is the consequence of underlying risk factors and comorbidities, which cannot be separated from AF alone,” Dr. Joglar explained in an interview.
This was placed first “to emphasize the importance of viewing AFib as a complex disease that requires a holistic, multidisciplinary approach to care, as opposed to being viewed just as a rhythm abnormality,” he said.
A version of this article first appeared on Medscape.com.
LONDON — Updated guidelines for the management of atrial fibrillation released by the European Society of Cardiology are revamping the approach to care for this complex, multifactorial disease.
, Isabelle Van Gelder, MD, PhD, professor of cardiology at the University Medical Center in Groningen, the Netherlands, explained at the European Society of Cardiology (ESC) Congress.
It is not just appropriate to place the same emphasis on the control of comorbidities as on the rhythm disturbance, it is critical, said Dr. Van Gelder, who served as chair of the ESC-AF guidelines task force.
Comorbidities are the drivers of both the onset and recurrence of atrial fibrillation, and a dynamic approach to comorbidities is “central for the success of AF management.”
Class I Recommendation
In fact, on the basis of overwhelming evidence, a class I recommendation has been issued for a large number of goals in the comorbidity and risk factor management step of atrial fibrillation management, including those for hypertension, components of heart failure, obesity, diabetes, alcohol consumption, and exercise.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors “should be offered to all patients with AF,” according to Dr. Van Gelder, who identified this as a new class I recommendation.
Patients who are not managed aggressively for the listed comorbidities ultimately face “treatment failure, poor patient outcomes, and a waste of healthcare resources,” she said.
Control of sleep apnea is also noted as a key target, although Van Gelder acknowledged that the supporting evidence only allows for a class IIb recommendation.
Control of comorbidities is not a new idea. In the 2023 joint guideline, led by a consortium of professional groups, including the American Heart Association (AHA) and the American College of Cardiology (ACC), the control of comorbidities, including most of those identified in the new ESC guidelines, was second in a list of 10 key take-home messages.
However, the new ESC guidelines have prioritized comorbidity management by listing it first in each of the specific patient-care pathways developed to define optimized care.
These pathways, defined in algorithms for newly diagnosed AF, paroxysmal AF, and persistent AF, always start with the assessment of comorbidities, followed by step A — avoiding stroke — largely with anticoagulation.
Direct oral anticoagulants should be used, “except in those with a mechanical valve or mitral stenosis,” Dr. Van Gelder said. This includes, essentially, all patients with a CHA2DS2-VASc score of 2 or greater, and it should be “considered” in those with a score of 1.
The ESC framework has been identified with the acronym AF-CARE, in which the C stands for comorbidities.
In the A step of the framework, identifying and treating all modifiable bleeding risk factors in AF patients is a class I recommendation. On the basis of a class III recommendation, she cautioned against withholding anticoagulants because of CHA2DS2-VASc risk factors alone. Rather, Dr. Van Gelder called the decision to administer or withhold anticoagulation — like all decisions — one that should be individualized in consultation with the patient.
For reducing AF symptoms and rhythm control, the specific pathways diverge for newly diagnosed AF, paroxysmal AF, and persistent AF. Like all of the guidelines, the specific options for symptom management and AF ablation are color coded, with green signifying level 1 evidence.
The evaluation and dynamic reassessment step refers to the need to periodically assess patients for new modifiable risk factors related to comorbidities, risk for stroke, risk for bleeding, and risk for AF.
The management of risk factors for AF has long been emphasized in guidelines, but a previous focus on AF with attention to comorbidities has been replaced by a focus on comorbidities with an expectation of more durable AF control. The success of this pivot is based on multidisciplinary care, chosen in collaboration with the patient, to reduce or eliminate the triggers of AF and the risks of its complications.
Pathways Are Appropriate for All Patients
A very important recommendation — and this is new — is “to treat all our patients with atrial fibrillation, whether they are young or old, men or women, Black or White, or at high or low risk, according to our patient-centered integrated AF-CARE approach,” Dr. Van Gelder said.
The changes reflect a shared appreciation for the tight relation between the control of comorbidities and the control of AF, according to José A. Joglar, MD, professor of cardiac electrophysiologic research at the University of Texas Southwestern Medical Center in Dallas. Dr. Joglar was chair of the writing committee for the joint 2023 AF guidelines released by the AHA, ACC, the American College of Clinical Pharmacy, and the Heart Rhythm Society.
“It is increasingly clear that AF in many cases is the consequence of underlying risk factors and comorbidities, which cannot be separated from AF alone,” Dr. Joglar explained in an interview.
This was placed first “to emphasize the importance of viewing AFib as a complex disease that requires a holistic, multidisciplinary approach to care, as opposed to being viewed just as a rhythm abnormality,” he said.
A version of this article first appeared on Medscape.com.
FROM ESC 2024
Less Invasive, Overlooked Option in Cardiac Surgery May Offer Benefit
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
Compared with traditional replacement valves, sutureless valves placed through minimally invasive cardiac surgery have less data supporting their use but offer unique features that might make them the preferred option for certain patients, reported specialists.
The sutureless device known as Perceval (Corcym) and a rapidly deployed device called Intuity (Edwards Lifesciences) are used as an alternative to surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). But despite being commercially available since 2016, the devices are still not being used much.
The devices are not discussed in substantial detail in either the joint guidelines from the American College of Cardiology and American Heart Association issued in 2020 or guidelines from the European Society of Cardiology issued in 2022.
Cristiano Spadaccio, MD, PhD, a cardiothoracic surgeon associated with Lancashire Cardiac Centre in Blackpool, England, and his colleagues reviewed the small number of studies evaluating the alternate approach to “make the cardiology world aware” of alternatives “that can relieve the surgical burden by minimizing the implantation time and length of the operation,” he said.
The comprehensive review is published in the Journal of the American College of Cardiology.
A Neglected Alternative
The sutureless Perceval device is held in place by a stent frame that self-expands. The Intuity device also relies primarily on its framework to anchor the valve in place but does involve three sutures. Both devices are still referred to as sutureless in the new review of them.
Only a small number of centers perform minimally invasive cardiac surgeries, and the main advantage of the devices — rapid deployment — has been eroded with the advent of automated knotting which has significantly reduced the time to implant and sutured valve.
The underuse of these devices is largely caused by the limited amount of comparative and prospective data, said Dr. Spadaccio. “The entire literature on sutureless aortic valve replacement with the exception of one randomized controlled trial is observational.”
That trial, PERSIST-AVR, found that the sutureless valves were just as good as conventional ones when it comes to major adverse cardiovascular events including all-cause death, myocardial infarction, stroke, or valve reintervention at 1 year.
In a subanalysis limited to patients who had isolated aortic valve replacement, the sutureless procedure was associated with lower adverse events (5.2% vs 10.8%) at the cost of a higher rate of pacemaker implantation (11% vs 1.6%).
There are also multiple retrospective studies and registries that have generated observational data comparing sutureless aortic valve replacement with SAVR and TAVR in various patient populations, said Dr. Spadaccio, and the review was based on more than a dozen studies published since 2015. Long-term follow-up data for sutureless aortic valve replacements, which now exceeds 10 years, suggest rates of structural valve deterioration and reintervention have been acceptably low.
The minimally invasive procedures have other advantages too. For example, relative to the greater trauma associated with open heart surgery, minimally invasive surgeries typically involve faster recovery, an advantage likely to appeal to many patients who are candidates for either.
Quicker Recovery
Collectively, these data suggest that sutureless aortic valve replacement might be a reasonable or even a more appropriate alternative to either SAVR or TAVR when considering specific patient characteristics and goals, according to the review, which included an algorithm identifying specifically where sutureless aortic valve replacement fits with SAVR and TAVR.
“The algorithm is based on different clinical scenarios and reflects current guidelines for SAVR,” said Dr. Spadaccio. For example, current guidelines identify SAVR as preferred in patients younger than 65 years and in older patients with a low Society of Thoracic Surgeons (STS) score, but there are many instances in which sutureless aortic valve replacement might be more attractive, such as in those also undergoing mitral valve repair, coronary artery bypass grafting, or another surgical procedure.
Dr. Spadaccio said that the STS score should not be considered in isolation when evaluating a patient for SAVR or TAVR. Other features such as mobility, frailty score, and comorbid liver or renal disease should also be considered when discussing the three options with patients. As a result, the algorithm emphasizes a detailed evaluation of patient characteristics in selecting one procedure over another.
“The treatment should be really tailored on the individual patient basis,” said Dr. Spadaccio.
Dr. Spadaccio acknowledged that there is a need for more comparative trials, particularly in regard to sutureless aortic valve replacement as an alternative to TAVR. “I really think that a 1:1 RCT on sutureless aortic valve replacement vs TAVR could give better answers to all of these interrogatives.”
But despite the limitations outlined in this review, Dr. Spadaccio and colleagues challenged the perception that current data are not sufficient to allow clinicians to consider sutureless aortic valve replacement in the mix of options.
A Viable Option
This comprehensive summary of what is known about sutureless aortic valve replacement compared with the other options addresses an important knowledge gap, said S. Chris Malaisrie, MD, a cardiac surgeon at Northwestern University Feinberg School of Medicine, Chicago, Illinois.
He said he agrees this option has unique qualities. “Minimally invasive surgery has been largely ignored by guideline writers, but patients certainly demand options that are less invasive than standard open heart surgery. Sutureless and rapid deployment valves facilitate minimally invasive surgery and offer an advantageous option for younger patients.”
Dr. Malaisrie said the review is generating discussion about a potentially valuable option within the cardiology community. And that is exactly what Dr. Spadaccio was hoping for. “This paper was meant to educate as much as possible on these details to assist and inform decision-making,” he said.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Gout Drugs in Late-Phase Trials Might Increase Patients at Target Urate Level
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
FROM EULAR 2024
CAR T-Cell Treatment Data Expands in Refractory Rheumatic Diseases, Demonstrating Consistent Efficacy
VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.
Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
SLE Is Frequently Targeted in CAR T-Cell Studies
The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.
The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.
For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.
All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
Remissions Have Persisted Off All Therapies
These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.
These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.
Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.
Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.
Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.
Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.
After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
CAR T-Cell Studies in Autoimmune Diseases Are Proliferating
At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.
At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.
Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.
For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
Complete B-Cell Depletion Is Followed by Full Recovery
“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.
Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.
Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.
In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.
cCAR T-Cell Construct Targets Immune Reset
With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.
B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.
However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.
The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.
Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.
Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.
Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.
Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.
“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.
Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
Other Case Series Presented at EULAR
Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:
Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.
Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.
Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented. Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.
August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.
A version of this article appeared on Medscape.com.
VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.
Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
SLE Is Frequently Targeted in CAR T-Cell Studies
The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.
The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.
For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.
All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
Remissions Have Persisted Off All Therapies
These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.
These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.
Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.
Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.
Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.
Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.
After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
CAR T-Cell Studies in Autoimmune Diseases Are Proliferating
At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.
At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.
Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.
For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
Complete B-Cell Depletion Is Followed by Full Recovery
“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.
Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.
Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.
In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.
cCAR T-Cell Construct Targets Immune Reset
With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.
B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.
However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.
The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.
Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.
Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.
Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.
Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.
“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.
Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
Other Case Series Presented at EULAR
Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:
Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.
Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.
Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented. Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.
August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.
A version of this article appeared on Medscape.com.
VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.
Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
SLE Is Frequently Targeted in CAR T-Cell Studies
The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.
The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.
For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.
All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
Remissions Have Persisted Off All Therapies
These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.
These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.
Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.
Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.
Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.
Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.
After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
CAR T-Cell Studies in Autoimmune Diseases Are Proliferating
At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.
At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.
Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.
For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
Complete B-Cell Depletion Is Followed by Full Recovery
“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.
Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.
Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.
In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.
cCAR T-Cell Construct Targets Immune Reset
With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.
B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.
However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.
The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.
Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.
Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.
Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.
Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.
“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.
Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
Other Case Series Presented at EULAR
Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:
Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.
Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.
Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented. Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.
August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.
A version of this article appeared on Medscape.com.
FROM EULAR 2024
Pediatric Studies Produce Mixed Messages on Relationship Between COVID and Asthma
In one of several recently published studies on the relationship between COVID-19 infection and asthma, according to data drawn from the National Survey of Children’s Health (NSCH).
The inverse correlation between symptoms and vaccination was strong and statistically significant, according to investigators led by Matthew M. Davis, MD, Physician in Chief and Chief Scientific Officer, Nemours Children’s Health, Wilmington, Delaware.
“With each increase of 10 percentage points in COVID-19 vaccination coverage, the parent-reported child asthma symptoms prevalence decreased by 0.36 percentage points (P < .05),” Dr. Davis and his coinvestigators reported in a research letter published in JAMA Network Open.
Studies Explore Relationship of COVID and Asthma
The reduced risk of asthma symptoms with COVID-19 vaccination in children at the population level is just one of several recently published studies exploring the interaction between COVID-19 infection and asthma, but two studies that posed the same question did not reach the same conclusion.
In one, COVID-19 infection in children was not found to be a trigger for new-onset asthma, but the second found that it was. In a third study, the preponderance of evidence from a meta-analysis found that patients with asthma – whether children or adults – did not necessarily experience a more severe course of COVID-19 infection than in those without asthma.
The NSCH database study calculated state-level change in scores for patient-reported childhood asthma symptoms in the years in the years 2018-2019, which preceded the pandemic and the years 2020-2021, when the pandemic began. The hypothesis was that the proportion of the population 5 years of age or older who completed the COVID-19 primary vaccination would be inversely related to asthma symptom prevalence.
Relative to the 2018-2019 years, the mean rate of parent-reported asthma symptoms was 0.85% lower (6.93% vs 7.77%; P < .001) in 2020-2021, when the mean primary series COVID-19 vaccination rate was 72.3%.
The study was not able to evaluate the impact of COVID-19 vaccination specifically in children with asthma, because history of asthma is not captured in the NSCH data, but Dr. Davis contended that the reduction in symptomatic asthma among children with increased vaccination offers validation for the state-level findings.
“Moreover, the absence of an association of COVID-19 vaccination administered predominantly in 2021 with population-level COVID-19 mortality in 2020 serves as a negative control,” he and his colleagues wrote in their research letter.
Protection from Respiratory Viruses Seen for Asthma Patients
In an interview, Dr. Davis reported that these data are consistent with previous evidence that immunization against influenza also reduces risk of asthma symptoms. In a meta-analysis published in 2017, it was estimated that live vaccines reduced risk of influenza by 81% and prevented 59%-72% of asthma attacks leading to hospitalizations or emergency room visits.
“The similarity of our findings regarding COVID-19 vaccination to prior data regarding influenza vaccination underscores the importance of preventing viral illnesses in individuals with a history of asthma,” Dr. Davis said. It is not yet clear if this is true of respiratory syncytial virus (RSV). Because of the short time that the RSV vaccine has been available, it is too soon to conduct an analysis.
One message from this study is that “clinicians should continue to encourage COVID-19 vaccination for children because of its general benefits in preventing coronavirus-related illness and the apparent specific benefits for children with a history of asthma,” he said.
While vaccination appears to reduce asthmatic symptoms related to COVID-19 infection, one study suggests that COVID-19 does not trigger new-onset asthma. In a retrospective study published in Pediatrics, no association between COVID-19 infection and new-onset asthma could be made in an analysis of 27,423 children (ages, 1-16 years) from the Children’s Hospital of Philadelphia (CHOP) Care Network.
Across all the pediatric age groups evaluated, the consistent finding was “SARS-CoV-2 positivity does not confer an additional risk for asthma diagnosis at least within the first 18 months after a [polymerase chain reaction] test,” concluded the investigators, led by David A. Hill, MD, PhD, Division of Allergy and Immunology, CHOP, Philadelphia, Pennsylvania.
Risk of Asthma Doubled After COVID-19 Infection
However, the opposite conclusion was reached by investigators evaluating data from two cohorts of children ages 5-18 drawn from the TriNetX database, a global health research network with data on more than 250 million individuals. Cohort 1 included more than 250,000 children. These children had never received COVID-19 vaccination. The 50,000 patients in cohort 2 had all received COVID19 vaccination.
To compare the impact of COVID-19 infection on new-onset asthma, the patients who were infected with COVID-19 were compared with those who were not infected after propensity score matching over 18 months of follow-up.
In cohort 1, the rate of new onset asthma was more than twofold greater among those with COVID-19 infection (4.7% vs 2.0%). The hazard ratio (HR) of 2.25 had tight confidence intervals (95% CI, 2.158-2.367).
In cohort 2, the risk of new-onset asthma at 18 months among those who had a COVID-19 infection relative to those without was even greater (8.3% vs 3.1%). The relative risk approached a 3-fold increase (HR 2.745; 95% CI, 2.521-2.99).
The conclusion of these investigators, led by Chia-Chi Lung, PhD, Department of Public Health, Chung Shan Medical University, Taichung City, Taiwan, was that there is “a critical need for ongoing monitoring and customized healthcare strategies to mitigate the long-term respiratory impacts of COVID-19 in children.”
These health risks might not be as significant as once feared. In the recently published study from Environmental Health Insights, the goal of a meta-analysis was to determine if patients with asthma relative to those without asthma face a higher risk of serious disease from COVID-19 infection. The meta-analysis included studies of children and adults. The answer, according an in-depth analysis of 21 articles in a “scoping review,” was a qualified no.
Of the 21 articles, 4 concluded that asthma is a risk factor for serious COVID-19 infection, but 17 did not, according to Chukwudi S. Ubah, PhD, Department of Public Health, Brody School of Medicine, East Caroline University, Greenville, North Carolina.
None of These Questions are Fully Resolved
However, given the disparity in the results and the fact that many of the studies included in this analysis had small sample sizes, Dr. Ubah called for larger studies and studies with better controls. He noted, for example, that the studies did not consistently evaluate mitigating factors, such as used of inhaled or oral corticosteroids, which might affect risk of the severity of a COVID-19 infection.
Rather, “our findings pointed out that the type of medication prescribed for asthma may have implications for the severity of COVID-19 infection in these patients,” Dr. Ubah said in an interview.
Overall, the data do not support a major interaction between asthma and COVID-19, even if the data are not conclusive. Each of the senior authors of these studies called for larger and better investigations to further explore whether COVID-19 infection and preexisting asthma interact. So far, the data indicate that if COVID-19 infection poses a risk of precipitating new-onset asthma or inducing a more severe infection in children with asthma, it is low, but the degree of risk, if any, remains unresolved in subgroups defined by asthma treatment or asthma severity.
Dr. Davis, Dr. Hill, Dr. Lung, and Dr. Ubah reported no potential conflicts of interest. None of these studies received funding from commercial interests.
In one of several recently published studies on the relationship between COVID-19 infection and asthma, according to data drawn from the National Survey of Children’s Health (NSCH).
The inverse correlation between symptoms and vaccination was strong and statistically significant, according to investigators led by Matthew M. Davis, MD, Physician in Chief and Chief Scientific Officer, Nemours Children’s Health, Wilmington, Delaware.
“With each increase of 10 percentage points in COVID-19 vaccination coverage, the parent-reported child asthma symptoms prevalence decreased by 0.36 percentage points (P < .05),” Dr. Davis and his coinvestigators reported in a research letter published in JAMA Network Open.
Studies Explore Relationship of COVID and Asthma
The reduced risk of asthma symptoms with COVID-19 vaccination in children at the population level is just one of several recently published studies exploring the interaction between COVID-19 infection and asthma, but two studies that posed the same question did not reach the same conclusion.
In one, COVID-19 infection in children was not found to be a trigger for new-onset asthma, but the second found that it was. In a third study, the preponderance of evidence from a meta-analysis found that patients with asthma – whether children or adults – did not necessarily experience a more severe course of COVID-19 infection than in those without asthma.
The NSCH database study calculated state-level change in scores for patient-reported childhood asthma symptoms in the years in the years 2018-2019, which preceded the pandemic and the years 2020-2021, when the pandemic began. The hypothesis was that the proportion of the population 5 years of age or older who completed the COVID-19 primary vaccination would be inversely related to asthma symptom prevalence.
Relative to the 2018-2019 years, the mean rate of parent-reported asthma symptoms was 0.85% lower (6.93% vs 7.77%; P < .001) in 2020-2021, when the mean primary series COVID-19 vaccination rate was 72.3%.
The study was not able to evaluate the impact of COVID-19 vaccination specifically in children with asthma, because history of asthma is not captured in the NSCH data, but Dr. Davis contended that the reduction in symptomatic asthma among children with increased vaccination offers validation for the state-level findings.
“Moreover, the absence of an association of COVID-19 vaccination administered predominantly in 2021 with population-level COVID-19 mortality in 2020 serves as a negative control,” he and his colleagues wrote in their research letter.
Protection from Respiratory Viruses Seen for Asthma Patients
In an interview, Dr. Davis reported that these data are consistent with previous evidence that immunization against influenza also reduces risk of asthma symptoms. In a meta-analysis published in 2017, it was estimated that live vaccines reduced risk of influenza by 81% and prevented 59%-72% of asthma attacks leading to hospitalizations or emergency room visits.
“The similarity of our findings regarding COVID-19 vaccination to prior data regarding influenza vaccination underscores the importance of preventing viral illnesses in individuals with a history of asthma,” Dr. Davis said. It is not yet clear if this is true of respiratory syncytial virus (RSV). Because of the short time that the RSV vaccine has been available, it is too soon to conduct an analysis.
One message from this study is that “clinicians should continue to encourage COVID-19 vaccination for children because of its general benefits in preventing coronavirus-related illness and the apparent specific benefits for children with a history of asthma,” he said.
While vaccination appears to reduce asthmatic symptoms related to COVID-19 infection, one study suggests that COVID-19 does not trigger new-onset asthma. In a retrospective study published in Pediatrics, no association between COVID-19 infection and new-onset asthma could be made in an analysis of 27,423 children (ages, 1-16 years) from the Children’s Hospital of Philadelphia (CHOP) Care Network.
Across all the pediatric age groups evaluated, the consistent finding was “SARS-CoV-2 positivity does not confer an additional risk for asthma diagnosis at least within the first 18 months after a [polymerase chain reaction] test,” concluded the investigators, led by David A. Hill, MD, PhD, Division of Allergy and Immunology, CHOP, Philadelphia, Pennsylvania.
Risk of Asthma Doubled After COVID-19 Infection
However, the opposite conclusion was reached by investigators evaluating data from two cohorts of children ages 5-18 drawn from the TriNetX database, a global health research network with data on more than 250 million individuals. Cohort 1 included more than 250,000 children. These children had never received COVID-19 vaccination. The 50,000 patients in cohort 2 had all received COVID19 vaccination.
To compare the impact of COVID-19 infection on new-onset asthma, the patients who were infected with COVID-19 were compared with those who were not infected after propensity score matching over 18 months of follow-up.
In cohort 1, the rate of new onset asthma was more than twofold greater among those with COVID-19 infection (4.7% vs 2.0%). The hazard ratio (HR) of 2.25 had tight confidence intervals (95% CI, 2.158-2.367).
In cohort 2, the risk of new-onset asthma at 18 months among those who had a COVID-19 infection relative to those without was even greater (8.3% vs 3.1%). The relative risk approached a 3-fold increase (HR 2.745; 95% CI, 2.521-2.99).
The conclusion of these investigators, led by Chia-Chi Lung, PhD, Department of Public Health, Chung Shan Medical University, Taichung City, Taiwan, was that there is “a critical need for ongoing monitoring and customized healthcare strategies to mitigate the long-term respiratory impacts of COVID-19 in children.”
These health risks might not be as significant as once feared. In the recently published study from Environmental Health Insights, the goal of a meta-analysis was to determine if patients with asthma relative to those without asthma face a higher risk of serious disease from COVID-19 infection. The meta-analysis included studies of children and adults. The answer, according an in-depth analysis of 21 articles in a “scoping review,” was a qualified no.
Of the 21 articles, 4 concluded that asthma is a risk factor for serious COVID-19 infection, but 17 did not, according to Chukwudi S. Ubah, PhD, Department of Public Health, Brody School of Medicine, East Caroline University, Greenville, North Carolina.
None of These Questions are Fully Resolved
However, given the disparity in the results and the fact that many of the studies included in this analysis had small sample sizes, Dr. Ubah called for larger studies and studies with better controls. He noted, for example, that the studies did not consistently evaluate mitigating factors, such as used of inhaled or oral corticosteroids, which might affect risk of the severity of a COVID-19 infection.
Rather, “our findings pointed out that the type of medication prescribed for asthma may have implications for the severity of COVID-19 infection in these patients,” Dr. Ubah said in an interview.
Overall, the data do not support a major interaction between asthma and COVID-19, even if the data are not conclusive. Each of the senior authors of these studies called for larger and better investigations to further explore whether COVID-19 infection and preexisting asthma interact. So far, the data indicate that if COVID-19 infection poses a risk of precipitating new-onset asthma or inducing a more severe infection in children with asthma, it is low, but the degree of risk, if any, remains unresolved in subgroups defined by asthma treatment or asthma severity.
Dr. Davis, Dr. Hill, Dr. Lung, and Dr. Ubah reported no potential conflicts of interest. None of these studies received funding from commercial interests.
In one of several recently published studies on the relationship between COVID-19 infection and asthma, according to data drawn from the National Survey of Children’s Health (NSCH).
The inverse correlation between symptoms and vaccination was strong and statistically significant, according to investigators led by Matthew M. Davis, MD, Physician in Chief and Chief Scientific Officer, Nemours Children’s Health, Wilmington, Delaware.
“With each increase of 10 percentage points in COVID-19 vaccination coverage, the parent-reported child asthma symptoms prevalence decreased by 0.36 percentage points (P < .05),” Dr. Davis and his coinvestigators reported in a research letter published in JAMA Network Open.
Studies Explore Relationship of COVID and Asthma
The reduced risk of asthma symptoms with COVID-19 vaccination in children at the population level is just one of several recently published studies exploring the interaction between COVID-19 infection and asthma, but two studies that posed the same question did not reach the same conclusion.
In one, COVID-19 infection in children was not found to be a trigger for new-onset asthma, but the second found that it was. In a third study, the preponderance of evidence from a meta-analysis found that patients with asthma – whether children or adults – did not necessarily experience a more severe course of COVID-19 infection than in those without asthma.
The NSCH database study calculated state-level change in scores for patient-reported childhood asthma symptoms in the years in the years 2018-2019, which preceded the pandemic and the years 2020-2021, when the pandemic began. The hypothesis was that the proportion of the population 5 years of age or older who completed the COVID-19 primary vaccination would be inversely related to asthma symptom prevalence.
Relative to the 2018-2019 years, the mean rate of parent-reported asthma symptoms was 0.85% lower (6.93% vs 7.77%; P < .001) in 2020-2021, when the mean primary series COVID-19 vaccination rate was 72.3%.
The study was not able to evaluate the impact of COVID-19 vaccination specifically in children with asthma, because history of asthma is not captured in the NSCH data, but Dr. Davis contended that the reduction in symptomatic asthma among children with increased vaccination offers validation for the state-level findings.
“Moreover, the absence of an association of COVID-19 vaccination administered predominantly in 2021 with population-level COVID-19 mortality in 2020 serves as a negative control,” he and his colleagues wrote in their research letter.
Protection from Respiratory Viruses Seen for Asthma Patients
In an interview, Dr. Davis reported that these data are consistent with previous evidence that immunization against influenza also reduces risk of asthma symptoms. In a meta-analysis published in 2017, it was estimated that live vaccines reduced risk of influenza by 81% and prevented 59%-72% of asthma attacks leading to hospitalizations or emergency room visits.
“The similarity of our findings regarding COVID-19 vaccination to prior data regarding influenza vaccination underscores the importance of preventing viral illnesses in individuals with a history of asthma,” Dr. Davis said. It is not yet clear if this is true of respiratory syncytial virus (RSV). Because of the short time that the RSV vaccine has been available, it is too soon to conduct an analysis.
One message from this study is that “clinicians should continue to encourage COVID-19 vaccination for children because of its general benefits in preventing coronavirus-related illness and the apparent specific benefits for children with a history of asthma,” he said.
While vaccination appears to reduce asthmatic symptoms related to COVID-19 infection, one study suggests that COVID-19 does not trigger new-onset asthma. In a retrospective study published in Pediatrics, no association between COVID-19 infection and new-onset asthma could be made in an analysis of 27,423 children (ages, 1-16 years) from the Children’s Hospital of Philadelphia (CHOP) Care Network.
Across all the pediatric age groups evaluated, the consistent finding was “SARS-CoV-2 positivity does not confer an additional risk for asthma diagnosis at least within the first 18 months after a [polymerase chain reaction] test,” concluded the investigators, led by David A. Hill, MD, PhD, Division of Allergy and Immunology, CHOP, Philadelphia, Pennsylvania.
Risk of Asthma Doubled After COVID-19 Infection
However, the opposite conclusion was reached by investigators evaluating data from two cohorts of children ages 5-18 drawn from the TriNetX database, a global health research network with data on more than 250 million individuals. Cohort 1 included more than 250,000 children. These children had never received COVID-19 vaccination. The 50,000 patients in cohort 2 had all received COVID19 vaccination.
To compare the impact of COVID-19 infection on new-onset asthma, the patients who were infected with COVID-19 were compared with those who were not infected after propensity score matching over 18 months of follow-up.
In cohort 1, the rate of new onset asthma was more than twofold greater among those with COVID-19 infection (4.7% vs 2.0%). The hazard ratio (HR) of 2.25 had tight confidence intervals (95% CI, 2.158-2.367).
In cohort 2, the risk of new-onset asthma at 18 months among those who had a COVID-19 infection relative to those without was even greater (8.3% vs 3.1%). The relative risk approached a 3-fold increase (HR 2.745; 95% CI, 2.521-2.99).
The conclusion of these investigators, led by Chia-Chi Lung, PhD, Department of Public Health, Chung Shan Medical University, Taichung City, Taiwan, was that there is “a critical need for ongoing monitoring and customized healthcare strategies to mitigate the long-term respiratory impacts of COVID-19 in children.”
These health risks might not be as significant as once feared. In the recently published study from Environmental Health Insights, the goal of a meta-analysis was to determine if patients with asthma relative to those without asthma face a higher risk of serious disease from COVID-19 infection. The meta-analysis included studies of children and adults. The answer, according an in-depth analysis of 21 articles in a “scoping review,” was a qualified no.
Of the 21 articles, 4 concluded that asthma is a risk factor for serious COVID-19 infection, but 17 did not, according to Chukwudi S. Ubah, PhD, Department of Public Health, Brody School of Medicine, East Caroline University, Greenville, North Carolina.
None of These Questions are Fully Resolved
However, given the disparity in the results and the fact that many of the studies included in this analysis had small sample sizes, Dr. Ubah called for larger studies and studies with better controls. He noted, for example, that the studies did not consistently evaluate mitigating factors, such as used of inhaled or oral corticosteroids, which might affect risk of the severity of a COVID-19 infection.
Rather, “our findings pointed out that the type of medication prescribed for asthma may have implications for the severity of COVID-19 infection in these patients,” Dr. Ubah said in an interview.
Overall, the data do not support a major interaction between asthma and COVID-19, even if the data are not conclusive. Each of the senior authors of these studies called for larger and better investigations to further explore whether COVID-19 infection and preexisting asthma interact. So far, the data indicate that if COVID-19 infection poses a risk of precipitating new-onset asthma or inducing a more severe infection in children with asthma, it is low, but the degree of risk, if any, remains unresolved in subgroups defined by asthma treatment or asthma severity.
Dr. Davis, Dr. Hill, Dr. Lung, and Dr. Ubah reported no potential conflicts of interest. None of these studies received funding from commercial interests.
FROM JAMA NETWORK OPEN
First-line Canakinumab Without Steroids Shows Effectiveness for Systemic Juvenile Idiopathic Arthritis
VIENNA — The interleukin-1 receptor antagonist (IL-1RA) canakinumab provided control of systemic juvenile idiopathic arthritis (sJIA) without the use of glucocorticoids for up to a year in most study participants after three monthly injections.
In this study of 20 patients with newly diagnosed sJIA treated off glucocorticoids, fever was controlled after a single injection in all patients, and 16 patients reached the primary outcome of remission after three injections, said Gerd Horneff, MD, PhD, Asklepios Children’s Hospital, Sankt Augustin, Germany.
Results of this open-label study, called CANAKINUMAB FIRST, were presented as late-breaking findings at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting.
“Steroid-free, first-line treatment with canakinumab led to sustained responses in most patients, with a considerable number achieving remission,” said Dr. Horneff, adding that the observation in this group is ongoing.
Building on Earlier Data
The efficacy of canakinumab was previously reported in anecdotal experiences and one small patient series published 10 years ago. Dr. Horneff noted that he has offered this drug off label to patients with challenging cases.
The objective was to evaluate canakinumab as a first-line monotherapy administered in the absence of glucocorticoids. The study was open to children aged 2-18 years with active sJIA/juvenile Still disease confirmed with published criteria. All were naive to biologic or nonbiologic disease-modifying antirheumatic drugs as well as steroids.
The median age of the children was 8.4 years. A total of 60% were men. The median disease duration at the time of entry was 1.2 months. Most had fever (95%) and rash (80%) with high levels of inflammatory markers at baseline. The mean number of painful joints was 3.1, and the mean number of systemic manifestations was 2.8. No patient was without any systemic involvement, but four of the patients did not have any painful joints.
At enrollment, patients were scheduled to receive three injections of canakinumab at monthly intervals during an active treatment phase, after which they entered an observation phase lasting 40 weeks. In the event of nonresponse or flares in either phase, they were transitioned to usual care.
Symptoms Resolve After Single Injection
After the first injection, active joint disease and all systemic manifestations resolved in 16 (80%) of the 20 patients. Joint activity and systemic manifestations also remained controlled after the second and third injections in 16 of the 20 patients.
One patient in this series achieved inactive disease after a single injection but developed what appeared to be a treatment-related allergic reaction. He received no further treatment and was excluded from the study, although he is being followed separately.
“According to sJADAS [systemic JIA Disease Activity Score] criteria at month 3, 14 had inactive disease, three had minimal disease activity, and one patient had moderate disease activity,” Dr. Horneff said.
At week 24, or 3 months after the last injection, there was still no joint activity in 16 patients. Systemic manifestations remained controlled in 13 patients, but 1 patient by this point had a flare. Another flare occurred after this point, and other patients have not yet completed the 52-week observation period.
“Of the 10 patients who remained in the study and have completed the 52-week observation period, eight have had a drug-free remission,” Dr. Horneff said.
MAS Event Observed in One Patient
In addition to the allergic skin reaction, which was considered probably related to the study drug, there were three flares, one of which was a macrophage activation syndrome (MAS) event. The MAS occurred 8 weeks after the last injection, but it was managed successfully.
Of 30 infections that developed during the observation period, 18 involved the upper airway. All were treated successfully. There were also two injection-site reactions and one case of cytopenia.
Among the studies planned for follow-up, investigators will examine genomic and gene activation in relation to disease activity and the effect of canakinumab.
Comoderator of the abstract session and chair of the EULAR 2024 Abstract Selection Committee, Christian Dejaco, MD, PhD, a consultant rheumatologist and associate professor at the Medical University of Graz in Graz, Austria, suggested that these are highly encouraging data for a disease that does not currently have any approved therapies. Clearly, larger studies with a longer follow-up period are needed, but he pointed out that phase 3 trials in a rare disease like sJIA are challenging.
Because of the limited number of cases, “it will be difficult to conduct a placebo-controlled trial,” he pointed out. However, he hopes this study will provide the basis for larger studies and sufficient data to lead to an indication for this therapy.
In the meantime, he also believes that these data are likely to support empirical use in a difficult disease, even in advance of formal regulatory approval.
“We heard that canakinumab is already being used off label in JIA, and these data might encourage more of that,” he said.
Dr. Horneff reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Chugai, GlaxoSmithKline, Janssen, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobe. Dr. Dejaco reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — The interleukin-1 receptor antagonist (IL-1RA) canakinumab provided control of systemic juvenile idiopathic arthritis (sJIA) without the use of glucocorticoids for up to a year in most study participants after three monthly injections.
In this study of 20 patients with newly diagnosed sJIA treated off glucocorticoids, fever was controlled after a single injection in all patients, and 16 patients reached the primary outcome of remission after three injections, said Gerd Horneff, MD, PhD, Asklepios Children’s Hospital, Sankt Augustin, Germany.
Results of this open-label study, called CANAKINUMAB FIRST, were presented as late-breaking findings at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting.
“Steroid-free, first-line treatment with canakinumab led to sustained responses in most patients, with a considerable number achieving remission,” said Dr. Horneff, adding that the observation in this group is ongoing.
Building on Earlier Data
The efficacy of canakinumab was previously reported in anecdotal experiences and one small patient series published 10 years ago. Dr. Horneff noted that he has offered this drug off label to patients with challenging cases.
The objective was to evaluate canakinumab as a first-line monotherapy administered in the absence of glucocorticoids. The study was open to children aged 2-18 years with active sJIA/juvenile Still disease confirmed with published criteria. All were naive to biologic or nonbiologic disease-modifying antirheumatic drugs as well as steroids.
The median age of the children was 8.4 years. A total of 60% were men. The median disease duration at the time of entry was 1.2 months. Most had fever (95%) and rash (80%) with high levels of inflammatory markers at baseline. The mean number of painful joints was 3.1, and the mean number of systemic manifestations was 2.8. No patient was without any systemic involvement, but four of the patients did not have any painful joints.
At enrollment, patients were scheduled to receive three injections of canakinumab at monthly intervals during an active treatment phase, after which they entered an observation phase lasting 40 weeks. In the event of nonresponse or flares in either phase, they were transitioned to usual care.
Symptoms Resolve After Single Injection
After the first injection, active joint disease and all systemic manifestations resolved in 16 (80%) of the 20 patients. Joint activity and systemic manifestations also remained controlled after the second and third injections in 16 of the 20 patients.
One patient in this series achieved inactive disease after a single injection but developed what appeared to be a treatment-related allergic reaction. He received no further treatment and was excluded from the study, although he is being followed separately.
“According to sJADAS [systemic JIA Disease Activity Score] criteria at month 3, 14 had inactive disease, three had minimal disease activity, and one patient had moderate disease activity,” Dr. Horneff said.
At week 24, or 3 months after the last injection, there was still no joint activity in 16 patients. Systemic manifestations remained controlled in 13 patients, but 1 patient by this point had a flare. Another flare occurred after this point, and other patients have not yet completed the 52-week observation period.
“Of the 10 patients who remained in the study and have completed the 52-week observation period, eight have had a drug-free remission,” Dr. Horneff said.
MAS Event Observed in One Patient
In addition to the allergic skin reaction, which was considered probably related to the study drug, there were three flares, one of which was a macrophage activation syndrome (MAS) event. The MAS occurred 8 weeks after the last injection, but it was managed successfully.
Of 30 infections that developed during the observation period, 18 involved the upper airway. All were treated successfully. There were also two injection-site reactions and one case of cytopenia.
Among the studies planned for follow-up, investigators will examine genomic and gene activation in relation to disease activity and the effect of canakinumab.
Comoderator of the abstract session and chair of the EULAR 2024 Abstract Selection Committee, Christian Dejaco, MD, PhD, a consultant rheumatologist and associate professor at the Medical University of Graz in Graz, Austria, suggested that these are highly encouraging data for a disease that does not currently have any approved therapies. Clearly, larger studies with a longer follow-up period are needed, but he pointed out that phase 3 trials in a rare disease like sJIA are challenging.
Because of the limited number of cases, “it will be difficult to conduct a placebo-controlled trial,” he pointed out. However, he hopes this study will provide the basis for larger studies and sufficient data to lead to an indication for this therapy.
In the meantime, he also believes that these data are likely to support empirical use in a difficult disease, even in advance of formal regulatory approval.
“We heard that canakinumab is already being used off label in JIA, and these data might encourage more of that,” he said.
Dr. Horneff reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Chugai, GlaxoSmithKline, Janssen, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobe. Dr. Dejaco reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — The interleukin-1 receptor antagonist (IL-1RA) canakinumab provided control of systemic juvenile idiopathic arthritis (sJIA) without the use of glucocorticoids for up to a year in most study participants after three monthly injections.
In this study of 20 patients with newly diagnosed sJIA treated off glucocorticoids, fever was controlled after a single injection in all patients, and 16 patients reached the primary outcome of remission after three injections, said Gerd Horneff, MD, PhD, Asklepios Children’s Hospital, Sankt Augustin, Germany.
Results of this open-label study, called CANAKINUMAB FIRST, were presented as late-breaking findings at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting.
“Steroid-free, first-line treatment with canakinumab led to sustained responses in most patients, with a considerable number achieving remission,” said Dr. Horneff, adding that the observation in this group is ongoing.
Building on Earlier Data
The efficacy of canakinumab was previously reported in anecdotal experiences and one small patient series published 10 years ago. Dr. Horneff noted that he has offered this drug off label to patients with challenging cases.
The objective was to evaluate canakinumab as a first-line monotherapy administered in the absence of glucocorticoids. The study was open to children aged 2-18 years with active sJIA/juvenile Still disease confirmed with published criteria. All were naive to biologic or nonbiologic disease-modifying antirheumatic drugs as well as steroids.
The median age of the children was 8.4 years. A total of 60% were men. The median disease duration at the time of entry was 1.2 months. Most had fever (95%) and rash (80%) with high levels of inflammatory markers at baseline. The mean number of painful joints was 3.1, and the mean number of systemic manifestations was 2.8. No patient was without any systemic involvement, but four of the patients did not have any painful joints.
At enrollment, patients were scheduled to receive three injections of canakinumab at monthly intervals during an active treatment phase, after which they entered an observation phase lasting 40 weeks. In the event of nonresponse or flares in either phase, they were transitioned to usual care.
Symptoms Resolve After Single Injection
After the first injection, active joint disease and all systemic manifestations resolved in 16 (80%) of the 20 patients. Joint activity and systemic manifestations also remained controlled after the second and third injections in 16 of the 20 patients.
One patient in this series achieved inactive disease after a single injection but developed what appeared to be a treatment-related allergic reaction. He received no further treatment and was excluded from the study, although he is being followed separately.
“According to sJADAS [systemic JIA Disease Activity Score] criteria at month 3, 14 had inactive disease, three had minimal disease activity, and one patient had moderate disease activity,” Dr. Horneff said.
At week 24, or 3 months after the last injection, there was still no joint activity in 16 patients. Systemic manifestations remained controlled in 13 patients, but 1 patient by this point had a flare. Another flare occurred after this point, and other patients have not yet completed the 52-week observation period.
“Of the 10 patients who remained in the study and have completed the 52-week observation period, eight have had a drug-free remission,” Dr. Horneff said.
MAS Event Observed in One Patient
In addition to the allergic skin reaction, which was considered probably related to the study drug, there were three flares, one of which was a macrophage activation syndrome (MAS) event. The MAS occurred 8 weeks after the last injection, but it was managed successfully.
Of 30 infections that developed during the observation period, 18 involved the upper airway. All were treated successfully. There were also two injection-site reactions and one case of cytopenia.
Among the studies planned for follow-up, investigators will examine genomic and gene activation in relation to disease activity and the effect of canakinumab.
Comoderator of the abstract session and chair of the EULAR 2024 Abstract Selection Committee, Christian Dejaco, MD, PhD, a consultant rheumatologist and associate professor at the Medical University of Graz in Graz, Austria, suggested that these are highly encouraging data for a disease that does not currently have any approved therapies. Clearly, larger studies with a longer follow-up period are needed, but he pointed out that phase 3 trials in a rare disease like sJIA are challenging.
Because of the limited number of cases, “it will be difficult to conduct a placebo-controlled trial,” he pointed out. However, he hopes this study will provide the basis for larger studies and sufficient data to lead to an indication for this therapy.
In the meantime, he also believes that these data are likely to support empirical use in a difficult disease, even in advance of formal regulatory approval.
“We heard that canakinumab is already being used off label in JIA, and these data might encourage more of that,” he said.
Dr. Horneff reported financial relationships with AbbVie, Boehringer Ingelheim, Celgene, Chugai, GlaxoSmithKline, Janssen, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobe. Dr. Dejaco reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM EULAR 2024
Nurse-Led Care for Gout Generates Best Uric Acid Control
VIENNA — To maintain gout in remission, nurses in a rheumatology service do better than doctors in implementing a straightforward treat-to-target (T2T) strategy, according to a randomized study that showed a consistent advantage across subgroups.
“Our study provides evidence that nurse-led therapy for gout leads to better uric acid control, which is an important consideration with the increasing incidence and the increasing costs of managing this condition,” said Jesper W. Larsen, a registered nurse affiliated with the Department of Rheumatology at North Denmark Regional Hospital, Hjørring, Denmark. He presented the study at the annual European Congress of Rheumatology.
The advantage of nurse-led care was seen across every subgroup evaluated. Moreover, more patients in the nurse-led group than in the usual care group remained on urate-lowering therapy at the end of the 2-year study.
The optimal management of gout is based on the treatment goal of lowering serum uric acid (sUA) to below the physiologic level of 0.36 mmol/L (6 mg/dL), a strategy called T2T that is endorsed by both EULAR and the American College of Rheumatology.
“This target can be reached in most patients with commonly used therapies, including allopurinol, which is relatively inexpensive,” Mr. Larsen said. Given that disease control and sustained remission are largely based on this target, he and his colleagues tested the hypothesis that nurses working in a rheumatology service could provide efficient and cost-effective care.
A total of 286 patients with gout defined by microscopy who were treated between 2015 and 2021 were enrolled in the study. Of these, 100 patients who had been enrolled before the introduction of nurse-led care received and were maintained on usual care, which generally included diagnosis by an orthopedist, an emergency room physician, or an internist, with subsequent treatment and follow-up with a general practitioner.
Of 186 patients treated after nurse-led care was implemented, 72 were transitioned to usual care, and the remaining 114 continued receiving nurse-led care over the next 2 years of follow-up. In the nurse-led care arm, nurses who specialized in rheumatology and were trained in gout management monitored a structured T2T strategy. They were available for consultation, provided patient education, and followed laboratory values, including sUA, which they used to adjust treatments.
Except in the case of complications, “there was no more contact with physicians” once care was transferred to the nurse, Mr. Larsen said. Most of the nurse management was based on sUA laboratory values and performed by telephone.
At 2 years, 112 patients in the nurse-led care group were compared with the 144 in the usual care group. Two of the 114 patients who entered the nurse-care cohort and 28 of the 172 in the usual care cohort died before the study ended.
(83% vs 44%). This was also true of patients aged 70 years or older (84% vs 45%), patients with tophi (60% vs 33%), and patients with sUA > 0.5 mmol/L at baseline (84% vs 44%). Nurse-led care also kept a greater proportion of patients at target who entered the study with an estimated glomerular filtration rate < 60 mL/min per 1.73 m2 (84% vs 52%) or were taking diuretics (89% vs 52%). All differences reached statistical significance (P < .05).
The reason for the lower mortality at 2 years in the nurse-led group (4% vs 23%; P < .001) is unclear, according to Mr. Larsen. In addition to considering a selection bias that might have channeled patients with more severe disease to usual care, he and his coinvestigators are also considering whether the lower rates of sUA control in the usual care group might have led to a higher rate of cardiovascular events.
Because of some baseline imbalances, a selection bias cannot be ruled out, but the imbalances did not uniformly favor nurse-led care. For example, the proportion of patients with diabetes (23% vs 13%) or a baseline cancer diagnosis (11% vs 5%) was higher in the nurse-led care group. The proportion of patients with atrial fibrillation (45% vs 35%) or on diuretics (47% vs 33%) at baseline was higher in the usual care group.
The median age of 69 years was the same in the two groups, although the nurse-led group included a higher proportion of men to women (86% vs 76%).
Within a T2T strategy, nurses focused on reaching the target might do a better job than physicians in consistently monitoring and adjusting therapies as needed, but Mr. Larsen also speculated that nurses might offer a more collaborative approach and provide greater support through patient education and regular telephone contact.
Potential Advantages of Nurse-Led Care
Clinicians concerned about nurses missing nuances in disease progression or being slow to recognize complications might be surprised to learn about the advantage of nurse-led care, but Mwidimi Ndosi, PhD, an associate professor in rheumatology nursing at the University of the West of England, Bristol, England, was not.
“There is quite a large literature to show that nursing care is often superior to physician-led patient management in the appropriate circumstances,” Mr. Ndosi said. In this specific instance of gout management, he said that the treatment target is clear, and nurses are often able to devote more time to a specific goal, like T2T, than clinicians balancing more priorities.
“In this trial, the care was administered by nurse specialists who presumably are skilled in this disease and know their limitations if a consultation with a physician is needed,” he said.
Mr. Ndosi, like Mr. Larsen, considers it likely that nurse-led programs for a T2T gout protocol will be implemented elsewhere. Mr. Ndosi pointed out that patients who are concerned about the quality of nurse-led care are generally convinced of its merits over time.
Because of factors such as nurses’ ability to spend more clinical time with patients and greater willingness to engage in resolving obstacles to self-care, compared with physicians, “there are many studies to show that patients are often more satisfied with care provided by nurses,” he said.
Mr. Larsen and Mr. Ndosi reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — To maintain gout in remission, nurses in a rheumatology service do better than doctors in implementing a straightforward treat-to-target (T2T) strategy, according to a randomized study that showed a consistent advantage across subgroups.
“Our study provides evidence that nurse-led therapy for gout leads to better uric acid control, which is an important consideration with the increasing incidence and the increasing costs of managing this condition,” said Jesper W. Larsen, a registered nurse affiliated with the Department of Rheumatology at North Denmark Regional Hospital, Hjørring, Denmark. He presented the study at the annual European Congress of Rheumatology.
The advantage of nurse-led care was seen across every subgroup evaluated. Moreover, more patients in the nurse-led group than in the usual care group remained on urate-lowering therapy at the end of the 2-year study.
The optimal management of gout is based on the treatment goal of lowering serum uric acid (sUA) to below the physiologic level of 0.36 mmol/L (6 mg/dL), a strategy called T2T that is endorsed by both EULAR and the American College of Rheumatology.
“This target can be reached in most patients with commonly used therapies, including allopurinol, which is relatively inexpensive,” Mr. Larsen said. Given that disease control and sustained remission are largely based on this target, he and his colleagues tested the hypothesis that nurses working in a rheumatology service could provide efficient and cost-effective care.
A total of 286 patients with gout defined by microscopy who were treated between 2015 and 2021 were enrolled in the study. Of these, 100 patients who had been enrolled before the introduction of nurse-led care received and were maintained on usual care, which generally included diagnosis by an orthopedist, an emergency room physician, or an internist, with subsequent treatment and follow-up with a general practitioner.
Of 186 patients treated after nurse-led care was implemented, 72 were transitioned to usual care, and the remaining 114 continued receiving nurse-led care over the next 2 years of follow-up. In the nurse-led care arm, nurses who specialized in rheumatology and were trained in gout management monitored a structured T2T strategy. They were available for consultation, provided patient education, and followed laboratory values, including sUA, which they used to adjust treatments.
Except in the case of complications, “there was no more contact with physicians” once care was transferred to the nurse, Mr. Larsen said. Most of the nurse management was based on sUA laboratory values and performed by telephone.
At 2 years, 112 patients in the nurse-led care group were compared with the 144 in the usual care group. Two of the 114 patients who entered the nurse-care cohort and 28 of the 172 in the usual care cohort died before the study ended.
(83% vs 44%). This was also true of patients aged 70 years or older (84% vs 45%), patients with tophi (60% vs 33%), and patients with sUA > 0.5 mmol/L at baseline (84% vs 44%). Nurse-led care also kept a greater proportion of patients at target who entered the study with an estimated glomerular filtration rate < 60 mL/min per 1.73 m2 (84% vs 52%) or were taking diuretics (89% vs 52%). All differences reached statistical significance (P < .05).
The reason for the lower mortality at 2 years in the nurse-led group (4% vs 23%; P < .001) is unclear, according to Mr. Larsen. In addition to considering a selection bias that might have channeled patients with more severe disease to usual care, he and his coinvestigators are also considering whether the lower rates of sUA control in the usual care group might have led to a higher rate of cardiovascular events.
Because of some baseline imbalances, a selection bias cannot be ruled out, but the imbalances did not uniformly favor nurse-led care. For example, the proportion of patients with diabetes (23% vs 13%) or a baseline cancer diagnosis (11% vs 5%) was higher in the nurse-led care group. The proportion of patients with atrial fibrillation (45% vs 35%) or on diuretics (47% vs 33%) at baseline was higher in the usual care group.
The median age of 69 years was the same in the two groups, although the nurse-led group included a higher proportion of men to women (86% vs 76%).
Within a T2T strategy, nurses focused on reaching the target might do a better job than physicians in consistently monitoring and adjusting therapies as needed, but Mr. Larsen also speculated that nurses might offer a more collaborative approach and provide greater support through patient education and regular telephone contact.
Potential Advantages of Nurse-Led Care
Clinicians concerned about nurses missing nuances in disease progression or being slow to recognize complications might be surprised to learn about the advantage of nurse-led care, but Mwidimi Ndosi, PhD, an associate professor in rheumatology nursing at the University of the West of England, Bristol, England, was not.
“There is quite a large literature to show that nursing care is often superior to physician-led patient management in the appropriate circumstances,” Mr. Ndosi said. In this specific instance of gout management, he said that the treatment target is clear, and nurses are often able to devote more time to a specific goal, like T2T, than clinicians balancing more priorities.
“In this trial, the care was administered by nurse specialists who presumably are skilled in this disease and know their limitations if a consultation with a physician is needed,” he said.
Mr. Ndosi, like Mr. Larsen, considers it likely that nurse-led programs for a T2T gout protocol will be implemented elsewhere. Mr. Ndosi pointed out that patients who are concerned about the quality of nurse-led care are generally convinced of its merits over time.
Because of factors such as nurses’ ability to spend more clinical time with patients and greater willingness to engage in resolving obstacles to self-care, compared with physicians, “there are many studies to show that patients are often more satisfied with care provided by nurses,” he said.
Mr. Larsen and Mr. Ndosi reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — To maintain gout in remission, nurses in a rheumatology service do better than doctors in implementing a straightforward treat-to-target (T2T) strategy, according to a randomized study that showed a consistent advantage across subgroups.
“Our study provides evidence that nurse-led therapy for gout leads to better uric acid control, which is an important consideration with the increasing incidence and the increasing costs of managing this condition,” said Jesper W. Larsen, a registered nurse affiliated with the Department of Rheumatology at North Denmark Regional Hospital, Hjørring, Denmark. He presented the study at the annual European Congress of Rheumatology.
The advantage of nurse-led care was seen across every subgroup evaluated. Moreover, more patients in the nurse-led group than in the usual care group remained on urate-lowering therapy at the end of the 2-year study.
The optimal management of gout is based on the treatment goal of lowering serum uric acid (sUA) to below the physiologic level of 0.36 mmol/L (6 mg/dL), a strategy called T2T that is endorsed by both EULAR and the American College of Rheumatology.
“This target can be reached in most patients with commonly used therapies, including allopurinol, which is relatively inexpensive,” Mr. Larsen said. Given that disease control and sustained remission are largely based on this target, he and his colleagues tested the hypothesis that nurses working in a rheumatology service could provide efficient and cost-effective care.
A total of 286 patients with gout defined by microscopy who were treated between 2015 and 2021 were enrolled in the study. Of these, 100 patients who had been enrolled before the introduction of nurse-led care received and were maintained on usual care, which generally included diagnosis by an orthopedist, an emergency room physician, or an internist, with subsequent treatment and follow-up with a general practitioner.
Of 186 patients treated after nurse-led care was implemented, 72 were transitioned to usual care, and the remaining 114 continued receiving nurse-led care over the next 2 years of follow-up. In the nurse-led care arm, nurses who specialized in rheumatology and were trained in gout management monitored a structured T2T strategy. They were available for consultation, provided patient education, and followed laboratory values, including sUA, which they used to adjust treatments.
Except in the case of complications, “there was no more contact with physicians” once care was transferred to the nurse, Mr. Larsen said. Most of the nurse management was based on sUA laboratory values and performed by telephone.
At 2 years, 112 patients in the nurse-led care group were compared with the 144 in the usual care group. Two of the 114 patients who entered the nurse-care cohort and 28 of the 172 in the usual care cohort died before the study ended.
(83% vs 44%). This was also true of patients aged 70 years or older (84% vs 45%), patients with tophi (60% vs 33%), and patients with sUA > 0.5 mmol/L at baseline (84% vs 44%). Nurse-led care also kept a greater proportion of patients at target who entered the study with an estimated glomerular filtration rate < 60 mL/min per 1.73 m2 (84% vs 52%) or were taking diuretics (89% vs 52%). All differences reached statistical significance (P < .05).
The reason for the lower mortality at 2 years in the nurse-led group (4% vs 23%; P < .001) is unclear, according to Mr. Larsen. In addition to considering a selection bias that might have channeled patients with more severe disease to usual care, he and his coinvestigators are also considering whether the lower rates of sUA control in the usual care group might have led to a higher rate of cardiovascular events.
Because of some baseline imbalances, a selection bias cannot be ruled out, but the imbalances did not uniformly favor nurse-led care. For example, the proportion of patients with diabetes (23% vs 13%) or a baseline cancer diagnosis (11% vs 5%) was higher in the nurse-led care group. The proportion of patients with atrial fibrillation (45% vs 35%) or on diuretics (47% vs 33%) at baseline was higher in the usual care group.
The median age of 69 years was the same in the two groups, although the nurse-led group included a higher proportion of men to women (86% vs 76%).
Within a T2T strategy, nurses focused on reaching the target might do a better job than physicians in consistently monitoring and adjusting therapies as needed, but Mr. Larsen also speculated that nurses might offer a more collaborative approach and provide greater support through patient education and regular telephone contact.
Potential Advantages of Nurse-Led Care
Clinicians concerned about nurses missing nuances in disease progression or being slow to recognize complications might be surprised to learn about the advantage of nurse-led care, but Mwidimi Ndosi, PhD, an associate professor in rheumatology nursing at the University of the West of England, Bristol, England, was not.
“There is quite a large literature to show that nursing care is often superior to physician-led patient management in the appropriate circumstances,” Mr. Ndosi said. In this specific instance of gout management, he said that the treatment target is clear, and nurses are often able to devote more time to a specific goal, like T2T, than clinicians balancing more priorities.
“In this trial, the care was administered by nurse specialists who presumably are skilled in this disease and know their limitations if a consultation with a physician is needed,” he said.
Mr. Ndosi, like Mr. Larsen, considers it likely that nurse-led programs for a T2T gout protocol will be implemented elsewhere. Mr. Ndosi pointed out that patients who are concerned about the quality of nurse-led care are generally convinced of its merits over time.
Because of factors such as nurses’ ability to spend more clinical time with patients and greater willingness to engage in resolving obstacles to self-care, compared with physicians, “there are many studies to show that patients are often more satisfied with care provided by nurses,” he said.
Mr. Larsen and Mr. Ndosi reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM EULAR 2024
Why Do Investigational OA Drugs Need Better Trial Endpoints? Lorecivivint Serves as an Example
VIENNA — The hypothesis that pivotal clinical trials for osteoarthritis (OA)-modifying therapies are not using appropriate designs or endpoints appears to be consistent with the recent failure of the phase 3 trial of the investigational agent lorecivivint, according to experts tackling this issue.
For the elusive target of disease-modifying OA drugs (DMOADs), “there have been a lot of developments in the last few years but so far a lot of disappointments,” said Francis Berenbaum, MD, PhD, head of the department of rheumatology, Saint-Antoine Hospital, Paris, France.
Disagreement on the target most likely to favorably alter the natural history of disease might be the key issue. Dr. Berenbaum considers it essential to determine which changes in the joint signify a favorable drug effect and will lead to what regulatory agencies consider a clinically meaningful benefit. These include improved function and long-term preservation of the joint, as well as symptom control.
Of primary targets to modify the course of OA, cartilage is not one of them, according to Dr. Berenbaum, who spoke in a session on DMOADs and regenerative OA therapies at the annual European Congress of Rheumatology.
OA Is Not a Cartilage-Only Disease
“There is now a big consensus that osteoarthritis is not a cartilage-only disease,” he said. Rather, he addressed the inadequate appreciation of the “whole joint” pathology that underlies OA. He called for a fundamental “paradigm change” to work toward a disease-modifying effect that produces benefit on a hard endpoint.
There are multiple steps needed to work toward this goal after a consensus is reached on a meaningful surrogate endpoint, Dr. Berenbaum said. While symptom reduction is a good start, he called for evidence of disease attenuation or a regenerative effect on an important surrogate such as improved integrity of synovial tissue and improved bone health. Such surrogates are necessary to guide DMOAD development but not sufficient. The proof that a therapy is a DMOAD depends on a favorable effect on a hard endpoint. In the case of the knee, freedom from joint replacement is an example, Dr. Berenbaum said.
Philip G. Conaghan, MBBS, PhD, director of rheumatic and musculoskeletal medicine, University of Leeds, England, agreed with this general premise. Speaking just before Dr. Berenbaum in the same session, Dr. Conaghan traced this history of the effort to create DMOADs and updated those in clinical trials.
In his talk, he listed some of the many disappointments, including those which have targeted cartilage thickness, before updating the numerous ongoing development programs. There are many targets that appear viable, but none are in final stages of testing.
In remarks to this news organization, he said he generally agreed with Dr. Berenbaum about the need for greater rigor for developing drugs to meet regulatory criteria for disease-modifying effects.
Of the drugs he reviewed, Dr. Conaghan identified lorecivivint, an intra-articular CLK/DYRK inhibitor that’s thought to modulate Wnt and inflammatory pathways, as the only drug with DMOAD potential to go to a multicenter phase 3 trial so far. The drug’s negative outcome in phase 3 was particularly disappointing after the substantial promise shown in a phase 2b study published in 2021.
In the phase 3 study, lorecivivint, relative to placebo, did not achieve a significant improvement in the primary endpoint of improved medial joint space width (JSW) in the target knee as assessed at the end of a 48-week, double-blind trial.
New Follow-Up Data Support DMOAD Activity
Yet, additional extension data from the phase 3 lorecivivint trial presented in the EULAR DMOAD session challenge the conclusion even if they do not change the results.
The new data presented at EULAR is the second of two sets of extension data. The first, reported earlier, involved an analysis at 96 weeks or 48 weeks after the double-blind trial. At the beginning of this extension, lorecivivint-start patients had received a second intraarticular injection of 0.07 mg, while placebo patients were crossed over to receive their first injection.
Over the course of this first extension, the gradual loss in medial JSW observed from baseline to the end of the initial 48 weeks had plateaued in those treated with lorecivivint, but the decline continued in the placebo group. As a result, the lorecivivint-start patients had a numerical but not a statistically significant advantage for medial JSW over the placebo-switch group, according to Yusuf Yazici, MD, chief medical officer of Biosplice Therapeutics, San Diego, which developed lorecivivint.
In a second open-label extension described by Dr. Yazici at EULAR 2024, a third injection was administered to the lorecivivint-start patients and a second injection to the placebo-start patients. After 52 more weeks of follow-up, there were now 3 years of follow-up in the lorecivivint-start group and 2 years of follow-up in the placebo-start group.
At the end of this second extension, lorecivivint-start patients had a median increase in JSW that was approaching the baseline level at study entry. Although the placebo-start group had experienced a decline in the medial JSW at the end of the first extension when they had received one injection, JSW had also improved in the direction of baseline after a second injection with 2 years of follow-up. The advantage of three injections of lorecivivint over 3 years had now reached statistical significance (P = .031) despite the improvement seen in the placebo-start group following two injections over 2 years.
At 3 Years, Benefit Is Finally Potentially Significant
If placebo-treated patients had not received a second shot of lorecivivint and progressed at the rate seen before their second shot, the hypothetical trajectory would have provided lorecivivint with a highly statistically significant advantage (P < .001), said Dr. Yazici, displaying a hypothetical graph.
Along with improvements in pain and function associated with lorecivivint relative to placebo at 6 months, 12 months, and 24 months, the structural improvements in 3 years now suggest that “long-term treatment with lorecivivint has the potential to be a DMOAD for knee OA,” Dr. Yazici said.
While Dr. Berenbaum did not comment on this speculation, he did note the potential need for long-term studies to prove a disease-modifying effect in OA. This is the rationale for identifying surrogates.
To illustrate this point, Dr. Berenbaum made an analogy between OA and cardiovascular disease. In cardiovascular disease, surrogates of disease-modifying therapies, such as control of hypertension or hyperlipidemia, are accepted by regulatory agencies on the basis of their proven association with hard endpoints, such as myocardial infarction, stroke, or cardiovascular death. Like joint failure, these events can take years or decades to arise.
“For trials in OA, we need to agree on these surrogates,” Dr. Berenbaum said, although he acknowledged that they would then have to be validated. Noting that the US Food and Drug Administration has now identified OA as a serious disease for which accelerated drug approvals will be considered to address an unmet need, Dr. Berenbaum suggested there is an even greater impetus for improving strategies for DMOAD development.
Dr. Berenbaum reported financial relationships with Grünenthal, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, and Servier. Dr. Conaghan reported financial relationships with AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grünenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB. Dr. Yazici is an employee of Biosplice Therapeutics, which provided funding for the OAS-07 trial.
A version of this article first appeared on Medscape.com.
VIENNA — The hypothesis that pivotal clinical trials for osteoarthritis (OA)-modifying therapies are not using appropriate designs or endpoints appears to be consistent with the recent failure of the phase 3 trial of the investigational agent lorecivivint, according to experts tackling this issue.
For the elusive target of disease-modifying OA drugs (DMOADs), “there have been a lot of developments in the last few years but so far a lot of disappointments,” said Francis Berenbaum, MD, PhD, head of the department of rheumatology, Saint-Antoine Hospital, Paris, France.
Disagreement on the target most likely to favorably alter the natural history of disease might be the key issue. Dr. Berenbaum considers it essential to determine which changes in the joint signify a favorable drug effect and will lead to what regulatory agencies consider a clinically meaningful benefit. These include improved function and long-term preservation of the joint, as well as symptom control.
Of primary targets to modify the course of OA, cartilage is not one of them, according to Dr. Berenbaum, who spoke in a session on DMOADs and regenerative OA therapies at the annual European Congress of Rheumatology.
OA Is Not a Cartilage-Only Disease
“There is now a big consensus that osteoarthritis is not a cartilage-only disease,” he said. Rather, he addressed the inadequate appreciation of the “whole joint” pathology that underlies OA. He called for a fundamental “paradigm change” to work toward a disease-modifying effect that produces benefit on a hard endpoint.
There are multiple steps needed to work toward this goal after a consensus is reached on a meaningful surrogate endpoint, Dr. Berenbaum said. While symptom reduction is a good start, he called for evidence of disease attenuation or a regenerative effect on an important surrogate such as improved integrity of synovial tissue and improved bone health. Such surrogates are necessary to guide DMOAD development but not sufficient. The proof that a therapy is a DMOAD depends on a favorable effect on a hard endpoint. In the case of the knee, freedom from joint replacement is an example, Dr. Berenbaum said.
Philip G. Conaghan, MBBS, PhD, director of rheumatic and musculoskeletal medicine, University of Leeds, England, agreed with this general premise. Speaking just before Dr. Berenbaum in the same session, Dr. Conaghan traced this history of the effort to create DMOADs and updated those in clinical trials.
In his talk, he listed some of the many disappointments, including those which have targeted cartilage thickness, before updating the numerous ongoing development programs. There are many targets that appear viable, but none are in final stages of testing.
In remarks to this news organization, he said he generally agreed with Dr. Berenbaum about the need for greater rigor for developing drugs to meet regulatory criteria for disease-modifying effects.
Of the drugs he reviewed, Dr. Conaghan identified lorecivivint, an intra-articular CLK/DYRK inhibitor that’s thought to modulate Wnt and inflammatory pathways, as the only drug with DMOAD potential to go to a multicenter phase 3 trial so far. The drug’s negative outcome in phase 3 was particularly disappointing after the substantial promise shown in a phase 2b study published in 2021.
In the phase 3 study, lorecivivint, relative to placebo, did not achieve a significant improvement in the primary endpoint of improved medial joint space width (JSW) in the target knee as assessed at the end of a 48-week, double-blind trial.
New Follow-Up Data Support DMOAD Activity
Yet, additional extension data from the phase 3 lorecivivint trial presented in the EULAR DMOAD session challenge the conclusion even if they do not change the results.
The new data presented at EULAR is the second of two sets of extension data. The first, reported earlier, involved an analysis at 96 weeks or 48 weeks after the double-blind trial. At the beginning of this extension, lorecivivint-start patients had received a second intraarticular injection of 0.07 mg, while placebo patients were crossed over to receive their first injection.
Over the course of this first extension, the gradual loss in medial JSW observed from baseline to the end of the initial 48 weeks had plateaued in those treated with lorecivivint, but the decline continued in the placebo group. As a result, the lorecivivint-start patients had a numerical but not a statistically significant advantage for medial JSW over the placebo-switch group, according to Yusuf Yazici, MD, chief medical officer of Biosplice Therapeutics, San Diego, which developed lorecivivint.
In a second open-label extension described by Dr. Yazici at EULAR 2024, a third injection was administered to the lorecivivint-start patients and a second injection to the placebo-start patients. After 52 more weeks of follow-up, there were now 3 years of follow-up in the lorecivivint-start group and 2 years of follow-up in the placebo-start group.
At the end of this second extension, lorecivivint-start patients had a median increase in JSW that was approaching the baseline level at study entry. Although the placebo-start group had experienced a decline in the medial JSW at the end of the first extension when they had received one injection, JSW had also improved in the direction of baseline after a second injection with 2 years of follow-up. The advantage of three injections of lorecivivint over 3 years had now reached statistical significance (P = .031) despite the improvement seen in the placebo-start group following two injections over 2 years.
At 3 Years, Benefit Is Finally Potentially Significant
If placebo-treated patients had not received a second shot of lorecivivint and progressed at the rate seen before their second shot, the hypothetical trajectory would have provided lorecivivint with a highly statistically significant advantage (P < .001), said Dr. Yazici, displaying a hypothetical graph.
Along with improvements in pain and function associated with lorecivivint relative to placebo at 6 months, 12 months, and 24 months, the structural improvements in 3 years now suggest that “long-term treatment with lorecivivint has the potential to be a DMOAD for knee OA,” Dr. Yazici said.
While Dr. Berenbaum did not comment on this speculation, he did note the potential need for long-term studies to prove a disease-modifying effect in OA. This is the rationale for identifying surrogates.
To illustrate this point, Dr. Berenbaum made an analogy between OA and cardiovascular disease. In cardiovascular disease, surrogates of disease-modifying therapies, such as control of hypertension or hyperlipidemia, are accepted by regulatory agencies on the basis of their proven association with hard endpoints, such as myocardial infarction, stroke, or cardiovascular death. Like joint failure, these events can take years or decades to arise.
“For trials in OA, we need to agree on these surrogates,” Dr. Berenbaum said, although he acknowledged that they would then have to be validated. Noting that the US Food and Drug Administration has now identified OA as a serious disease for which accelerated drug approvals will be considered to address an unmet need, Dr. Berenbaum suggested there is an even greater impetus for improving strategies for DMOAD development.
Dr. Berenbaum reported financial relationships with Grünenthal, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, and Servier. Dr. Conaghan reported financial relationships with AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grünenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB. Dr. Yazici is an employee of Biosplice Therapeutics, which provided funding for the OAS-07 trial.
A version of this article first appeared on Medscape.com.
VIENNA — The hypothesis that pivotal clinical trials for osteoarthritis (OA)-modifying therapies are not using appropriate designs or endpoints appears to be consistent with the recent failure of the phase 3 trial of the investigational agent lorecivivint, according to experts tackling this issue.
For the elusive target of disease-modifying OA drugs (DMOADs), “there have been a lot of developments in the last few years but so far a lot of disappointments,” said Francis Berenbaum, MD, PhD, head of the department of rheumatology, Saint-Antoine Hospital, Paris, France.
Disagreement on the target most likely to favorably alter the natural history of disease might be the key issue. Dr. Berenbaum considers it essential to determine which changes in the joint signify a favorable drug effect and will lead to what regulatory agencies consider a clinically meaningful benefit. These include improved function and long-term preservation of the joint, as well as symptom control.
Of primary targets to modify the course of OA, cartilage is not one of them, according to Dr. Berenbaum, who spoke in a session on DMOADs and regenerative OA therapies at the annual European Congress of Rheumatology.
OA Is Not a Cartilage-Only Disease
“There is now a big consensus that osteoarthritis is not a cartilage-only disease,” he said. Rather, he addressed the inadequate appreciation of the “whole joint” pathology that underlies OA. He called for a fundamental “paradigm change” to work toward a disease-modifying effect that produces benefit on a hard endpoint.
There are multiple steps needed to work toward this goal after a consensus is reached on a meaningful surrogate endpoint, Dr. Berenbaum said. While symptom reduction is a good start, he called for evidence of disease attenuation or a regenerative effect on an important surrogate such as improved integrity of synovial tissue and improved bone health. Such surrogates are necessary to guide DMOAD development but not sufficient. The proof that a therapy is a DMOAD depends on a favorable effect on a hard endpoint. In the case of the knee, freedom from joint replacement is an example, Dr. Berenbaum said.
Philip G. Conaghan, MBBS, PhD, director of rheumatic and musculoskeletal medicine, University of Leeds, England, agreed with this general premise. Speaking just before Dr. Berenbaum in the same session, Dr. Conaghan traced this history of the effort to create DMOADs and updated those in clinical trials.
In his talk, he listed some of the many disappointments, including those which have targeted cartilage thickness, before updating the numerous ongoing development programs. There are many targets that appear viable, but none are in final stages of testing.
In remarks to this news organization, he said he generally agreed with Dr. Berenbaum about the need for greater rigor for developing drugs to meet regulatory criteria for disease-modifying effects.
Of the drugs he reviewed, Dr. Conaghan identified lorecivivint, an intra-articular CLK/DYRK inhibitor that’s thought to modulate Wnt and inflammatory pathways, as the only drug with DMOAD potential to go to a multicenter phase 3 trial so far. The drug’s negative outcome in phase 3 was particularly disappointing after the substantial promise shown in a phase 2b study published in 2021.
In the phase 3 study, lorecivivint, relative to placebo, did not achieve a significant improvement in the primary endpoint of improved medial joint space width (JSW) in the target knee as assessed at the end of a 48-week, double-blind trial.
New Follow-Up Data Support DMOAD Activity
Yet, additional extension data from the phase 3 lorecivivint trial presented in the EULAR DMOAD session challenge the conclusion even if they do not change the results.
The new data presented at EULAR is the second of two sets of extension data. The first, reported earlier, involved an analysis at 96 weeks or 48 weeks after the double-blind trial. At the beginning of this extension, lorecivivint-start patients had received a second intraarticular injection of 0.07 mg, while placebo patients were crossed over to receive their first injection.
Over the course of this first extension, the gradual loss in medial JSW observed from baseline to the end of the initial 48 weeks had plateaued in those treated with lorecivivint, but the decline continued in the placebo group. As a result, the lorecivivint-start patients had a numerical but not a statistically significant advantage for medial JSW over the placebo-switch group, according to Yusuf Yazici, MD, chief medical officer of Biosplice Therapeutics, San Diego, which developed lorecivivint.
In a second open-label extension described by Dr. Yazici at EULAR 2024, a third injection was administered to the lorecivivint-start patients and a second injection to the placebo-start patients. After 52 more weeks of follow-up, there were now 3 years of follow-up in the lorecivivint-start group and 2 years of follow-up in the placebo-start group.
At the end of this second extension, lorecivivint-start patients had a median increase in JSW that was approaching the baseline level at study entry. Although the placebo-start group had experienced a decline in the medial JSW at the end of the first extension when they had received one injection, JSW had also improved in the direction of baseline after a second injection with 2 years of follow-up. The advantage of three injections of lorecivivint over 3 years had now reached statistical significance (P = .031) despite the improvement seen in the placebo-start group following two injections over 2 years.
At 3 Years, Benefit Is Finally Potentially Significant
If placebo-treated patients had not received a second shot of lorecivivint and progressed at the rate seen before their second shot, the hypothetical trajectory would have provided lorecivivint with a highly statistically significant advantage (P < .001), said Dr. Yazici, displaying a hypothetical graph.
Along with improvements in pain and function associated with lorecivivint relative to placebo at 6 months, 12 months, and 24 months, the structural improvements in 3 years now suggest that “long-term treatment with lorecivivint has the potential to be a DMOAD for knee OA,” Dr. Yazici said.
While Dr. Berenbaum did not comment on this speculation, he did note the potential need for long-term studies to prove a disease-modifying effect in OA. This is the rationale for identifying surrogates.
To illustrate this point, Dr. Berenbaum made an analogy between OA and cardiovascular disease. In cardiovascular disease, surrogates of disease-modifying therapies, such as control of hypertension or hyperlipidemia, are accepted by regulatory agencies on the basis of their proven association with hard endpoints, such as myocardial infarction, stroke, or cardiovascular death. Like joint failure, these events can take years or decades to arise.
“For trials in OA, we need to agree on these surrogates,” Dr. Berenbaum said, although he acknowledged that they would then have to be validated. Noting that the US Food and Drug Administration has now identified OA as a serious disease for which accelerated drug approvals will be considered to address an unmet need, Dr. Berenbaum suggested there is an even greater impetus for improving strategies for DMOAD development.
Dr. Berenbaum reported financial relationships with Grünenthal, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, and Servier. Dr. Conaghan reported financial relationships with AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grünenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB. Dr. Yazici is an employee of Biosplice Therapeutics, which provided funding for the OAS-07 trial.
A version of this article first appeared on Medscape.com.
FROM EULAR 2024
Ixekizumab Met Phase 3 Trial Endpoint in Juvenile PsA, Enthesitis-Related Arthritis
VIENNA — Ixekizumab (Taltz), an interleukin-17A inhibitor that’s already approved for the treatment of psoriatic arthritis and axial spondyloarthritis in adults appears likely to be granted the same corresponding indications for children, based on initial results from an open-label, phase 3 trial that employed adalimumab as a reference.
With a safety profile comparable with that seen in adult patients, ixekizumab “met the prespecified criterion for success at 16 weeks,” reported Athimalaipet V. Ramanan, MD, PhD, of Bristol Royal Hospital for Children and Translational Health Sciences, Bristol, England.
In this multicenter, randomized, open-label trial called COSPIRIT-JIA, which is still ongoing, investigators enrolled 101 children with active juvenile PsA (JPsA) or enthesitis-related arthritis (ERA), which is akin to spondyloarthritis in adults.
The efficacy and safety data at 16 weeks were presented as a late-breaking abstract at the annual European Congress of Rheumatology. Dr. Ramanan said that the open-label extension to 104 weeks is underway and further follow-up out to 264 weeks is planned.
Nearly 90% Achieve ACR30
The trial had an adaptive design in which the first 40 patients without biologics experience were randomized to ixekizumab or adalimumab, stratified by JPsA or ERA diagnosis, and the following 61 patients with either no biologic experience or an inadequate response or intolerance to biologics all received ixekizumab. The drugs were dosed according to weight. Dr. Ramanan explained that a placebo-controlled trial was considered unethical because of the strong evidence of benefit from biologics for JPsA and ERA.
The trial easily met its predefined threshold for success, which required ≥ 80% probability, based on Bayesian analysis, that ≥ 50% of patients would have 30% improvement in American College of Rheumatology response criteria (ACR30) at week 16. ACR30 was achieved in 88.9% of those treated with ixekizumab overall vs 95.0% of those treated with adalimumab, but the trial was not designed as a head-to-head comparison. Rather, adalimumab served as a reference.
When compared for the distinct diseases, the ACR30 rates were also numerically lower for ixekizumab relative to adalimumab for both ERA (88.9% vs 93.8%) and JPsA (88.9% vs 100%), but all of the adalimumab patients were naive to biologics. In comparison, about 75% of patients receiving ixekizumab were biologic-therapy naive.
Response rates to ixekizumab overall were numerically higher for patients without previous biologic experience than for those with experience (90.0% vs 85.7%), and this was also the case for patients with ERA (92.5% vs 78.6%). However, in the JPsA group, biologic-experienced patients had higher numerical response rates to ixekizumab (100% vs 85.0%).
An ACR30 is not a clinical goal that satisfies most patients and clinicians, Dr. Ramanan conceded, but he noted that ACR50 was reached with ixekizumab by 81.5% with ERA and 74.1% with JPsA, and ACR70 was reached by 68.5% and 55.6%, respectively. The highest responses of ACR90 (27.8% and 33.3%) and ACR100 (14.8% and 25.9%) were lower but still substantial in the ERA and JPsA groups, respectively.
Through week 16, 58.0% of those treated with ixekizumab had an adverse event considered treatment-related. Nearly half were of mild severity, and the remainder were moderate. Only 3.7% were considered serious. No patient discontinued study treatment because of an adverse event.
In this study, the presence of at least three active peripheral joints was an inclusion criterion. The median age was about 13 years in the biologic-naive adalimumab and ixekizumab groups and 14 years in the ixekizumab biologic-experienced group. The youngest patient in the study was aged 5 years, and the oldest was aged 18 years. Although about 40% of patients were women in the two biologic-naive subgroups, it was 60% in the biologic-experienced group.
On average, patients in the biologic-naive group were entered about 1 year after diagnosis. In the experienced patients, the average duration of disease at entry was nearly 4 years. About 45% of patients remained on conventional synthetic disease-modifying antirheumatic drugs while receiving ixekizumab. The proportion was 35% in the adalimumab reference arm.
Ixekizumab Might Fulfill Need for More Options
There are several biologics that have received regulatory approval or are already widely used for the treatment of JPsA or ERA, but more options are needed, according to Dr. Ramanan and the chair of the abstract session in which these data were reported. According to Caroline Ospelt, MD, PhD, a researcher at the Center for Experimental Rheumatology, University Hospital Zurich, Switzerland, regulatory approval of ixekizumab will depend on sustained efficacy and safety in longer follow-up from the COSPIRIT-JIA trial, but this trial supports continued development.
Despite a novel mechanism of action, “the data so far suggest a level of efficacy similar to that of anti-TNF [anti-tumor necrosis factor] biologics,” said Dr. Ospelt, who, in addition to moderating the late-breaking session, served as Scientific Program Chair of EULAR 2024.
While Dr. Ospelt emphasized that she is a researcher involved in translational rheumatology studies and not a clinician, she said there was consensus within the program committee to select this abstract from other high-quality latebreaker submissions on the basis of its potential clinical significance.
Dr. Ramanan reported financial relationships with AbbVie, AstraZeneca, Novartis, Pfizer, Roche, SOBI, UCB, and Eli Lilly, which provided funding for this study. Dr. Ospelt reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — Ixekizumab (Taltz), an interleukin-17A inhibitor that’s already approved for the treatment of psoriatic arthritis and axial spondyloarthritis in adults appears likely to be granted the same corresponding indications for children, based on initial results from an open-label, phase 3 trial that employed adalimumab as a reference.
With a safety profile comparable with that seen in adult patients, ixekizumab “met the prespecified criterion for success at 16 weeks,” reported Athimalaipet V. Ramanan, MD, PhD, of Bristol Royal Hospital for Children and Translational Health Sciences, Bristol, England.
In this multicenter, randomized, open-label trial called COSPIRIT-JIA, which is still ongoing, investigators enrolled 101 children with active juvenile PsA (JPsA) or enthesitis-related arthritis (ERA), which is akin to spondyloarthritis in adults.
The efficacy and safety data at 16 weeks were presented as a late-breaking abstract at the annual European Congress of Rheumatology. Dr. Ramanan said that the open-label extension to 104 weeks is underway and further follow-up out to 264 weeks is planned.
Nearly 90% Achieve ACR30
The trial had an adaptive design in which the first 40 patients without biologics experience were randomized to ixekizumab or adalimumab, stratified by JPsA or ERA diagnosis, and the following 61 patients with either no biologic experience or an inadequate response or intolerance to biologics all received ixekizumab. The drugs were dosed according to weight. Dr. Ramanan explained that a placebo-controlled trial was considered unethical because of the strong evidence of benefit from biologics for JPsA and ERA.
The trial easily met its predefined threshold for success, which required ≥ 80% probability, based on Bayesian analysis, that ≥ 50% of patients would have 30% improvement in American College of Rheumatology response criteria (ACR30) at week 16. ACR30 was achieved in 88.9% of those treated with ixekizumab overall vs 95.0% of those treated with adalimumab, but the trial was not designed as a head-to-head comparison. Rather, adalimumab served as a reference.
When compared for the distinct diseases, the ACR30 rates were also numerically lower for ixekizumab relative to adalimumab for both ERA (88.9% vs 93.8%) and JPsA (88.9% vs 100%), but all of the adalimumab patients were naive to biologics. In comparison, about 75% of patients receiving ixekizumab were biologic-therapy naive.
Response rates to ixekizumab overall were numerically higher for patients without previous biologic experience than for those with experience (90.0% vs 85.7%), and this was also the case for patients with ERA (92.5% vs 78.6%). However, in the JPsA group, biologic-experienced patients had higher numerical response rates to ixekizumab (100% vs 85.0%).
An ACR30 is not a clinical goal that satisfies most patients and clinicians, Dr. Ramanan conceded, but he noted that ACR50 was reached with ixekizumab by 81.5% with ERA and 74.1% with JPsA, and ACR70 was reached by 68.5% and 55.6%, respectively. The highest responses of ACR90 (27.8% and 33.3%) and ACR100 (14.8% and 25.9%) were lower but still substantial in the ERA and JPsA groups, respectively.
Through week 16, 58.0% of those treated with ixekizumab had an adverse event considered treatment-related. Nearly half were of mild severity, and the remainder were moderate. Only 3.7% were considered serious. No patient discontinued study treatment because of an adverse event.
In this study, the presence of at least three active peripheral joints was an inclusion criterion. The median age was about 13 years in the biologic-naive adalimumab and ixekizumab groups and 14 years in the ixekizumab biologic-experienced group. The youngest patient in the study was aged 5 years, and the oldest was aged 18 years. Although about 40% of patients were women in the two biologic-naive subgroups, it was 60% in the biologic-experienced group.
On average, patients in the biologic-naive group were entered about 1 year after diagnosis. In the experienced patients, the average duration of disease at entry was nearly 4 years. About 45% of patients remained on conventional synthetic disease-modifying antirheumatic drugs while receiving ixekizumab. The proportion was 35% in the adalimumab reference arm.
Ixekizumab Might Fulfill Need for More Options
There are several biologics that have received regulatory approval or are already widely used for the treatment of JPsA or ERA, but more options are needed, according to Dr. Ramanan and the chair of the abstract session in which these data were reported. According to Caroline Ospelt, MD, PhD, a researcher at the Center for Experimental Rheumatology, University Hospital Zurich, Switzerland, regulatory approval of ixekizumab will depend on sustained efficacy and safety in longer follow-up from the COSPIRIT-JIA trial, but this trial supports continued development.
Despite a novel mechanism of action, “the data so far suggest a level of efficacy similar to that of anti-TNF [anti-tumor necrosis factor] biologics,” said Dr. Ospelt, who, in addition to moderating the late-breaking session, served as Scientific Program Chair of EULAR 2024.
While Dr. Ospelt emphasized that she is a researcher involved in translational rheumatology studies and not a clinician, she said there was consensus within the program committee to select this abstract from other high-quality latebreaker submissions on the basis of its potential clinical significance.
Dr. Ramanan reported financial relationships with AbbVie, AstraZeneca, Novartis, Pfizer, Roche, SOBI, UCB, and Eli Lilly, which provided funding for this study. Dr. Ospelt reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
VIENNA — Ixekizumab (Taltz), an interleukin-17A inhibitor that’s already approved for the treatment of psoriatic arthritis and axial spondyloarthritis in adults appears likely to be granted the same corresponding indications for children, based on initial results from an open-label, phase 3 trial that employed adalimumab as a reference.
With a safety profile comparable with that seen in adult patients, ixekizumab “met the prespecified criterion for success at 16 weeks,” reported Athimalaipet V. Ramanan, MD, PhD, of Bristol Royal Hospital for Children and Translational Health Sciences, Bristol, England.
In this multicenter, randomized, open-label trial called COSPIRIT-JIA, which is still ongoing, investigators enrolled 101 children with active juvenile PsA (JPsA) or enthesitis-related arthritis (ERA), which is akin to spondyloarthritis in adults.
The efficacy and safety data at 16 weeks were presented as a late-breaking abstract at the annual European Congress of Rheumatology. Dr. Ramanan said that the open-label extension to 104 weeks is underway and further follow-up out to 264 weeks is planned.
Nearly 90% Achieve ACR30
The trial had an adaptive design in which the first 40 patients without biologics experience were randomized to ixekizumab or adalimumab, stratified by JPsA or ERA diagnosis, and the following 61 patients with either no biologic experience or an inadequate response or intolerance to biologics all received ixekizumab. The drugs were dosed according to weight. Dr. Ramanan explained that a placebo-controlled trial was considered unethical because of the strong evidence of benefit from biologics for JPsA and ERA.
The trial easily met its predefined threshold for success, which required ≥ 80% probability, based on Bayesian analysis, that ≥ 50% of patients would have 30% improvement in American College of Rheumatology response criteria (ACR30) at week 16. ACR30 was achieved in 88.9% of those treated with ixekizumab overall vs 95.0% of those treated with adalimumab, but the trial was not designed as a head-to-head comparison. Rather, adalimumab served as a reference.
When compared for the distinct diseases, the ACR30 rates were also numerically lower for ixekizumab relative to adalimumab for both ERA (88.9% vs 93.8%) and JPsA (88.9% vs 100%), but all of the adalimumab patients were naive to biologics. In comparison, about 75% of patients receiving ixekizumab were biologic-therapy naive.
Response rates to ixekizumab overall were numerically higher for patients without previous biologic experience than for those with experience (90.0% vs 85.7%), and this was also the case for patients with ERA (92.5% vs 78.6%). However, in the JPsA group, biologic-experienced patients had higher numerical response rates to ixekizumab (100% vs 85.0%).
An ACR30 is not a clinical goal that satisfies most patients and clinicians, Dr. Ramanan conceded, but he noted that ACR50 was reached with ixekizumab by 81.5% with ERA and 74.1% with JPsA, and ACR70 was reached by 68.5% and 55.6%, respectively. The highest responses of ACR90 (27.8% and 33.3%) and ACR100 (14.8% and 25.9%) were lower but still substantial in the ERA and JPsA groups, respectively.
Through week 16, 58.0% of those treated with ixekizumab had an adverse event considered treatment-related. Nearly half were of mild severity, and the remainder were moderate. Only 3.7% were considered serious. No patient discontinued study treatment because of an adverse event.
In this study, the presence of at least three active peripheral joints was an inclusion criterion. The median age was about 13 years in the biologic-naive adalimumab and ixekizumab groups and 14 years in the ixekizumab biologic-experienced group. The youngest patient in the study was aged 5 years, and the oldest was aged 18 years. Although about 40% of patients were women in the two biologic-naive subgroups, it was 60% in the biologic-experienced group.
On average, patients in the biologic-naive group were entered about 1 year after diagnosis. In the experienced patients, the average duration of disease at entry was nearly 4 years. About 45% of patients remained on conventional synthetic disease-modifying antirheumatic drugs while receiving ixekizumab. The proportion was 35% in the adalimumab reference arm.
Ixekizumab Might Fulfill Need for More Options
There are several biologics that have received regulatory approval or are already widely used for the treatment of JPsA or ERA, but more options are needed, according to Dr. Ramanan and the chair of the abstract session in which these data were reported. According to Caroline Ospelt, MD, PhD, a researcher at the Center for Experimental Rheumatology, University Hospital Zurich, Switzerland, regulatory approval of ixekizumab will depend on sustained efficacy and safety in longer follow-up from the COSPIRIT-JIA trial, but this trial supports continued development.
Despite a novel mechanism of action, “the data so far suggest a level of efficacy similar to that of anti-TNF [anti-tumor necrosis factor] biologics,” said Dr. Ospelt, who, in addition to moderating the late-breaking session, served as Scientific Program Chair of EULAR 2024.
While Dr. Ospelt emphasized that she is a researcher involved in translational rheumatology studies and not a clinician, she said there was consensus within the program committee to select this abstract from other high-quality latebreaker submissions on the basis of its potential clinical significance.
Dr. Ramanan reported financial relationships with AbbVie, AstraZeneca, Novartis, Pfizer, Roche, SOBI, UCB, and Eli Lilly, which provided funding for this study. Dr. Ospelt reported no potential conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM EULAR 2024