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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
New EULAR lupus recommendations advise using biologics, tapering steroids
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
AT EULAR 2023
Patient selection key to lowering placebo response rates in lupus clinical trials
SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.
Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.
“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.
The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”
Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.
Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.
For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.
This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.
“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”
This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.
“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.
Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.
The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.
The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.
Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.
Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.
Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.
But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.
If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.
“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”
Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.
SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.
Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.
“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.
The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”
Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.
Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.
For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.
This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.
“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”
This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.
“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.
Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.
The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.
The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.
Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.
Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.
Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.
But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.
If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.
“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”
Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.
SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.
Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.
“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.
The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”
Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.
Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.
For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.
This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.
“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”
This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.
“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.
Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.
The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.
The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.
Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.
Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.
Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.
But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.
If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.
“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”
Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.
AT LUPUS 2023
Strategies for complete B-cell depletion evolve for patients with lupus nephritis
SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).
“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.
The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.
It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
More potent B-cell depletion with obinutuzumab
Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.
The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.
That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.
“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.
Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.
Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”
However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
Newer strategies for greater B-cell depletion
A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.
And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.
“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”
Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.
“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.
Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.
SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).
“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.
The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.
It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
More potent B-cell depletion with obinutuzumab
Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.
The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.
That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.
“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.
Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.
Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”
However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
Newer strategies for greater B-cell depletion
A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.
And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.
“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”
Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.
“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.
Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.
SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).
“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.
The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.
It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
More potent B-cell depletion with obinutuzumab
Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.
The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.
That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.
“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.
Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.
Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”
However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
Newer strategies for greater B-cell depletion
A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.
And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.
“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”
Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.
“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.
Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.
AT LUPUS 2023
In TNBC, repeated biopsies may reveal emergent HER2-low expression
Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. were found to be ineffective in patients with TNBC and known HER2-zero status.
These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).
Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."
“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.
In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).
Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.
Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.
At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.
The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.
“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.
After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.
She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.
Comoderator Michael Danso, MD, also weighed in when asked for comment.
“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.
Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.
*This story was updated on 6/13/2023.
Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. were found to be ineffective in patients with TNBC and known HER2-zero status.
These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).
Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."
“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.
In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).
Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.
Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.
At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.
The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.
“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.
After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.
She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.
Comoderator Michael Danso, MD, also weighed in when asked for comment.
“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.
Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.
*This story was updated on 6/13/2023.
Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. were found to be ineffective in patients with TNBC and known HER2-zero status.
These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).
Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."
“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.
In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).
Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.
Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.
At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.
The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.
“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.
After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.
She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.
Comoderator Michael Danso, MD, also weighed in when asked for comment.
“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.
Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.
*This story was updated on 6/13/2023.
FROM ASCO 2023
AI efforts make strides in predicting progression to RA
MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.
In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.
Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
RA prediction
Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”
Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”
The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.
The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.
The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.
“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”
“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
A ‘transitional phase’ of applying AI techniques
“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”
Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.
“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.
“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
Predicting disease progression
The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.
Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.
“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”
“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA] is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”
Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.
A version of this article first appeared on Medscape.com.
MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.
In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.
Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
RA prediction
Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”
Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”
The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.
The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.
The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.
“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”
“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
A ‘transitional phase’ of applying AI techniques
“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”
Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.
“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.
“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
Predicting disease progression
The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.
Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.
“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”
“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA] is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”
Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.
A version of this article first appeared on Medscape.com.
MILAN – Two independent efforts to use artificial intelligence (AI) to predict the development of early rheumatoid arthritis (RA) from patients with signs and symptoms not meeting full disease criteria showed good, near expert-level accuracy, according to findings from two studies presented at the annual European Congress of Rheumatology.
In one study, researchers from Leiden University Medical Center in the Netherlands developed an AI-based method to automatically analyze MR scans of extremities in order to predict early rheumatoid arthritis. The second study involved a Japanese research team that used machine learning to create a model capable of predicting progression from undifferentiated arthritis (UA) to RA. Both approaches would facilitate early diagnosis of RA, enabling timely treatment and improved clinical outcomes.
Lennart Jans, MD, PhD, who was not involved in either study but works with AI-assisted imaging analysis on a daily basis as head of clinics in musculoskeletal radiology at Ghent University Hospital and a professor of radiology at Ghent University in Belgium, said that integrating AI into health care poses several challenging aspects that need to be addressed. “There are three main challenges associated with the development and implementation of AI-based tools in clinical practice,” he said. “Firstly, obtaining heterogeneous datasets from different image hardware vendors, diverse racial and ethnic backgrounds, and various ages and genders is crucial for training and testing the AI algorithms. Secondly, AI algorithms need to achieve a predetermined performance level depending on the specific use case. Finally, a regulatory pathway must be followed to obtain the necessary FDA or MDR [medical devices regulation] certification before applying an AI use case in clinical practice.”
RA prediction
Yanli Li, the first author of the study and a member of the division of image processing at Leiden University Medical Center, explained the potential benefits of early RA prediction. “If we could determine whether a patient presenting with clinically suspected arthralgia (CSA) or early onset arthritis (EAC) is likely to develop RA in the near future, physicians could initiate treatment earlier, reducing the risk of disease progression.”
Currently, rheumatologists estimate the likelihood of developing RA by visually scoring MR scans using the RAMRIS scoring system. “We decided to explore the use of AI,” Dr. Li explained, “because it could save time, reduce costs and labor, eliminate the need for scoring training, and allow for hypothesis-free discoveries.”
The research team collected MR scans of the hands and feet from Leiden University Medical Center’s radiology department. The dataset consisted of images from 177 healthy individuals, 692 subjects with CSA (including 113 who developed RA), and 969 with EAC (including 447 who developed RA). The images underwent automated preprocessing to remove artifacts and standardize the input for the computer. Subsequently, a deep learning model was trained to predict RA development within a 2-year time frame.
The training process involved several steps. Initially, the researchers pretrained the model to learn anatomy by masking parts of the images and tasking the computer with reconstructing them. Subsequently, the AI was trained to differentiate between the groups (EAC vs. healthy and CSA vs. healthy), then between RA and other disorders. Finally, the AI model was trained to predict RA.
The accuracy of the model was evaluated using the area under the receiver operator characteristic curve (AUROC). The model that was trained using MR scans of the hands (including the wrist and metacarpophalangeal joints) achieved a mean AUROC of 0.84 for distinguishing EAC from healthy subjects and 0.83 for distinguishing CSA from healthy subjects. The model trained using MR scans of both the hands and feet achieved a mean AUROC of 0.71 for distinguishing RA from non-RA cases in EAC. The accuracy of the model in predicting RA using MR scans of the hands was 0.73, which closely matches the reported accuracy of visual scoring by human experts (0.74). Importantly, the generation and analysis of heat maps suggested that the deep learning model predicts RA based on known inflammatory signals.
“Automatic RA prediction using AI interpretation of MR scans is feasible,” Dr. Li said. “Incorporating additional clinical data will likely further enhance the AI prediction, and the heat maps may contribute to the discovery of new MRI biomarkers for RA development.”
“AI models and engines have achieved near-expertise levels for various use cases, including the early detection of RA on MRI scans of the hands,” said Dr. Jans, the Ghent University radiologist. “We are observing the same progress in AI detection of rheumatic diseases in other imaging modalities, such as radiography, CT, and ultrasound. However, it is important to note that the reported performances often apply to selected cohorts with standardized imaging protocols. The next challenge [for Dr. Li and colleagues, and others] will be to train and test these algorithms using more heterogeneous datasets to make them applicable in real-world settings.”
A ‘transitional phase’ of applying AI techniques
“In a medical setting, as computer scientists, we face unique challenges,” pointed out Berend C. Stoel, MSc, PhD, the senior author of the Leiden study. “Our team consists of approximately 30-35 researchers, primarily electrical engineers or computer scientists, situated within the radiology department of Leiden University Medical Center. Our focus is on image processing, seeking AI-based solutions for image analysis, particularly utilizing deep learning techniques.”
Their objective is to validate this method more broadly, and to achieve that, they require collaboration with other hospitals. Up until now, they have primarily worked with a specific type of MR images, extremity MR scans. These scans are conducted in only a few centers equipped with extremity MR scanners, which can accommodate only hands or feet.
“We are currently in a transitional phase, aiming to apply our methods to standard MR scans, which are more widely available,” Dr. Stoel informed this news organization. “We are engaged in various projects. One project, nearing completion, involves the scoring of early RA, where we train the computer to imitate the actions of rheumatologists or radiologists. We started with a relatively straightforward approach, but AI offers a multitude of possibilities. In the project presented at EULAR, we manipulated the images in a different manner, attempting to predict future events. We also have a parallel project where we employ AI to detect inflammatory changes over time by analyzing sequences of images (MR scans). Furthermore, we have developed AI models to distinguish between treatment and placebo groups. Once the neural network has been trained for this task, we can inquire about the location and timing of changes, thereby gaining insights into the therapy’s response.
“When considering the history of AI, it has experienced both ups and downs. We are currently in a promising phase, but if certain projects fail, expectations might diminish. My hope is that we will indeed revolutionize and enhance disease diagnosis, monitoring, and prediction. Additionally, AI may provide us with additional information that we, as humans, may not be able to extract from these images. However, it is difficult to predict where we will stand in 5-10 years,” he concluded.
Predicting disease progression
The second study, which explored the application of AI in predicting the progression of undifferentiated arthritis (UA) to RA, was presented by Takayuki Fujii, MD, PhD, assistant professor in the department of advanced medicine for rheumatic diseases at Kyoto University’s Graduate School of Medicine in Japan. “Predicting the progression of RA from UA remains an unmet medical need,” he reminded the audience.
Dr. Fujii’s team used data from the KURAMA cohort, a large observational RA cohort from a single center, to develop a machine learning model. The study included a total of 322 patients initially diagnosed with UA. The deep neural network (DNN) model was trained using 24 clinical features that are easily obtainable in routine clinical practice, such as age, sex, C-reactive protein (CRP) levels, and disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The DNN model achieved a prediction accuracy of 85.1% in the training cohort. When the model was applied to validation data from an external dataset consisting of 88 patients from the ANSWER cohort, a large multicenter observational RA cohort, the prediction accuracy was 80%.
“We have developed a machine learning model that can predict the progression of RA from UA using clinical parameters,” Dr. Fujii concluded. “This model has the potential to assist rheumatologists in providing appropriate care and timely intervention for patients with UA.”
“Dr. Fujii presented a fascinating study,” Dr. Jans said. “They achieved an accuracy of 80% when applying a DNN model to predict progression from UA to RA. This level of accuracy is relatively high and certainly promising. However, it is important to consider that a pre-test probability of 30% [for progressing from UA to RA] is also relatively high, which partially explains the high accuracy. Nonetheless, this study represents a significant step forward in the clinical management of patients with UA, as it helps identify those who may benefit the most from regular clinical follow-up.”
Dr. Li and Dr. Stoel report no relevant financial relationships with industry. Dr. Fujii has received speaking fees from Asahi Kasei, AbbVie, Chugai, and Tanabe Mitsubishi Pharma. Dr. Jans has received speaking fees from AbbVie, UCB, Lilly, and Novartis; he is cofounder of RheumaFinder. The Leiden study was funded by the Dutch Research Council and the China Scholarship Council. The study by Dr. Fujii and colleagues had no outside funding.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
RA and demyelinating disease: No consistent link to TNFi
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors (TNFi) does not appear to demonstrate a consistent and significant risk for demyelinating disease, according to a systematic literature review presented at the annual European Congress of Rheumatology.
The review was conducted by Isabel Castrejon, MD, of the rheumatology department at Gregorio Marañón General University Hospital, Madrid, and colleagues. “In male RA patients, a marginal and slight increase in risk was found. The low number of events provides reassurance regarding the use of these drugs. However, careful consideration is recommended for individuals at the highest risk of demyelinating diseases,” Dr. Castrejon said in an interview. “Health care providers should evaluate the potential benefits and risks of TNFi treatment on a case-by-case basis and closely monitor patients for any signs or symptoms of demyelinating events.”
The researchers performed the review because early data from biologic registries did not provide sufficient clarity, and the association between TNFi exposure and inflammatory central nervous system events remains poorly understood.
Key findings from the analyzed data
Dr. Castrejon and colleagues’ review considered 368 studies that included patients with RA, treatment with any biologic including TNFi and synthetic disease-modifying antirheumatic drugs (DMARDs), and demyelinating event.
The studies focused on assessing the risk of demyelinating events following treatment with biologics, particularly TNFi. Some studies included only patients with RA, while others examined mixed forms of arthritis. In cases involving mixed populations, patients with RA were analyzed separately. Additionally, certain studies solely considered multiple sclerosis, while others encompassed various types of demyelinating events. Dr. Castrejon said that a meta-analysis of the studies could not be performed because of their heterogeneity.
Among the 368 studies, four observational cohort studies and three nested case-control studies reported a risk of demyelinating events following treatment with biologics. Two nested case-control studies indicated an increased risk in mixed populations but did not separately analyze the subgroup of patients with RA. Two observational cohort studies revealed a marginally increased risk in men with RA who undergo TNFi treatment. In the first study, the incidence was 19.7/100,000 patient-years (95% confidence interval, 13.7-27.3) with a standardized incidence ratio of 1.38 (95% CI, 0.96-1.92), a definite case risk ratio of 0.83 (95% CI, 0.51-1.26), and an RR for male patients of 2.75 (95% CI, 1.31-5.06). The second study had an SIR of 1.11 (95% CI, 0.63-1.93), a RR for patients with RA of 0.65 (95% CI, 0.24-1.72), and male RR of 3.48 (95% CI, 1.45-8.37).
An unresolved question is whether demyelinating events are attributable to the underlying disease itself, which may not have been recognized at the time of diagnosis, or whether they are caused by DMARDs. Additionally, the articles that the reviewers analyzed did not consider patient characteristics that could interact with other factors, such as comorbidities or smoking, that might influence their susceptibility to the development of demyelinating events.
How should clinicians manage patients with RA who are at high risk of developing demyelinating diseases? “Typically, we initiate treatment with conventional synthetic disease-modifying methotrexate and then progress to other drugs,” Maya H. Buch, MBChB, PhD, professor of rheumatology at the University of Leeds (England), said in an interview. “For patients in high-risk groups, there are alternative treatment strategies, especially in comparison to TNFi, where there may be a rationale for their use.” Dr. Buch was not involved in the review.
Dr. Castrejon and colleagues reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
High-intensity interval training has sustainable effects in patients with inflammatory arthritis
MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.
Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.
Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
The trial
The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.
A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.
The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.
The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO2 max) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).
Following HIIT, a statistically significant difference was observed in VO2 max (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO2 max between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO2 max between the groups (3.2 mL/kg per min; P < .01).
Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
Long-lasting effects
Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”
There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.
Ms. Norden and coauthors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.
Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.
Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
The trial
The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.
A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.
The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.
The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO2 max) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).
Following HIIT, a statistically significant difference was observed in VO2 max (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO2 max between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO2 max between the groups (3.2 mL/kg per min; P < .01).
Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
Long-lasting effects
Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”
There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.
Ms. Norden and coauthors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MILAN – High-intensity interval training (HIIT) has been shown to enhance cardiorespiratory fitness (CRF) and mitigate cardiovascular disease (CVD) risk factors in patients with inflammatory joint diseases (IJD) in a randomized trial. Notably, the positive response in CRF did not coincide with changes in pain or fatigue.
Kristine Norden, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases, Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, presented the late-breaking results of the ExeHeart trial at the annual European Congress of Rheumatology. The trial aimed to evaluate the short- and long-term effects of 12 weeks of supervised HIIT in patients with IJD.
Ms. Norden said in an interview that “HIIT is a feasible physiotherapeutic intervention with sustainable effects in patients with IJD. It does not exacerbate symptoms of IJD and can be implemented in primary care settings.”
The trial
The ExeHeart trial is a randomized controlled trial designed to assess the effects of HIIT on CRF, CVD risk, and disease activity in patients with IJD. The trial is a collaborative effort with patient research partners and aligns with patients’ requests for effective nonpharmacologic treatments. The outcomes being evaluated include CRF (primary outcome), CVD risk factors, anthropometric measures, disease activity, and patient-reported outcomes related to pain, fatigue, disease, physical activity, and exercise.
A total of 60 patients with IJD were recruited from the Preventive Cardio-Rheuma clinic at Diakonhjemmet. They were randomly assigned to receive either standard care (including relevant lifestyle advice and cardiopreventive medication) or standard care along with a 12-week HIIT intervention supervised by physiotherapists. Assessments were conducted at baseline, at 3 months (primary endpoint), and at 6 months post baseline. There was no supervised intervention between the 3- and 6-month time points.
The median age of the participants was 59 years, with 34 participants (57%) being women. The types of IJD among the participants included rheumatoid arthritis in 45%, spondyloarthritis in 32%, and psoriatic arthritis in 23%. Furthermore, 49 patients (82%) had a high risk for CVD.
The participants were divided into two groups: a control group (n = 30) and a HIIT group (n = 30). The HIIT group underwent a 12-week intervention consisting of twice-a-week supervised 4x4-minute HIIT sessions at 90%-95% of peak heart rate, alternated with moderate activity at 70%. The control group engaged in unsupervised moderate-intensity exercise sessions. The primary outcome measured was the change in CRF, assessed through peak oxygen uptake (VO2 max) using a cardiopulmonary exercise test. Secondary outcomes – pain and fatigue – were evaluated using a questionnaire (Numeric Rating Scale 0-10, where 0 represents no pain or fatigue).
Following HIIT, a statistically significant difference was observed in VO2 max (2.5 mL/kg per min; P < .01) in favor of the exercise group at 3 months, while no significant differences were found in pain and fatigue. This discrepancy in VO2 max between the groups was maintained at 6 months (2.6 mL/kg per min; P < .01), with no notable disparities in pain and fatigue. A per-protocol analysis at 3 months demonstrated a difference in VO2 max between the groups (3.2 mL/kg per min; P < .01).
Ms. Norden concluded that the clinical implications of these findings are significant, as increased CRF achieved through HIIT reflects an improvement in the body’s ability to deliver oxygen to working muscles. Consequently, this enhancement in CRF can lead to overall health improvements and a reduced risk for CVD.
Long-lasting effects
Christopher Edwards, MBBS, MD, honorary consultant rheumatologist at University Hospital Southampton (England) NHS Foundation Trust Medicine, University of Southampton, was concerned about future maintenance of increased CRF. “I really wish we had data on these patients at 12 months as well, so we could see if the effects last even longer. Regarding intensity, there are clear indications that engaging in moderate and high-intensity workouts is more beneficial,” Dr. Norden said. “So, I would certainly recommend at least one high-intensity exercise session per week for those patients, while also incorporating lower and moderate-intensity exercises if desired. However, for individuals aiming to maximize their oxygen uptake, high-intensity exercise is considered the most effective approach.”
There is compelling evidence supporting the benefits of physical activity in improving disease activity among patients with IJD, making it a critical component of nonpharmacologic treatment. However, individuals with rheumatic and musculoskeletal conditions generally exhibit lower levels of physical activity, compared with their healthy counterparts. Recognizing the importance of CVD prevention in patients with IJD, EULAR recommends routine CVD screening for individuals diagnosed with IJD.
Ms. Norden and coauthors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
Pediatric Crohn’s disease: Adalimumab plus methotrexate offers strong benefit
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
FROM DDW 2023
No apparent drug interaction with ozanimod and antidepressants
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
DENVER – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.
“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
Clarifying the risk
“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.
“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
Examining open-label extension trial data
The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.
The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.
They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”
When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.
“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
A reassuring finding for clinicians and patients alike
“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”
The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
AT CMSC 2023
Breast cancer experts and other HCPs disagree on treatment strategies for early BC
The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.
Study methods and results
For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.
Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.
The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.
Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.
The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.
The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.
For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.
Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.
In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.
Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”
“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.
Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
Decision tool’s value explained
According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.
The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”
In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.
“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.
The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.
The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.
Study methods and results
For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.
Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.
The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.
Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.
The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.
The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.
For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.
Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.
In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.
Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”
“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.
Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
Decision tool’s value explained
According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.
The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”
In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.
“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.
The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.
The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.
Study methods and results
For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.
Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.
The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.
Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.
The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.
The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.
For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.
Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.
In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.
Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”
“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.
Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
Decision tool’s value explained
According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.
The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”
In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.
“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.
The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.
AT ASCO 2023