User login
MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
CAR-T in children branching out to solid tumors
Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.
In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.
Solid tumor studies
Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.
“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.
For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.
In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
Unresolved procedural questions
It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.
For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.
In the case tisagenlecleucel (Kymriah), his center typically collects 1x109 CD3 cells regardless of age or weight.
The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x106/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
Blinatumomab or inotuzumab?
Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.
Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.
The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.
Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
CD-19 expression
There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.
“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.
He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
Predicting relapse
Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.
“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.
The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
Transplant after CAR-T?
Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.
“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
Move CAR-T up front?
A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.
Dr. Yanik reported that he had no conflicts of interest to disclose.
Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.
In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.
Solid tumor studies
Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.
“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.
For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.
In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
Unresolved procedural questions
It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.
For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.
In the case tisagenlecleucel (Kymriah), his center typically collects 1x109 CD3 cells regardless of age or weight.
The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x106/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
Blinatumomab or inotuzumab?
Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.
Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.
The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.
Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
CD-19 expression
There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.
“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.
He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
Predicting relapse
Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.
“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.
The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
Transplant after CAR-T?
Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.
“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
Move CAR-T up front?
A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.
Dr. Yanik reported that he had no conflicts of interest to disclose.
Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.
In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.
Solid tumor studies
Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.
“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.
For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.
In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
Unresolved procedural questions
It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.
For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.
In the case tisagenlecleucel (Kymriah), his center typically collects 1x109 CD3 cells regardless of age or weight.
The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x106/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
Blinatumomab or inotuzumab?
Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.
Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.
The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.
Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
CD-19 expression
There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.
“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.
He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
Predicting relapse
Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.
“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.
The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
Transplant after CAR-T?
Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.
“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
Move CAR-T up front?
A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.
Dr. Yanik reported that he had no conflicts of interest to disclose.
FROM TCT 2021
RA experts highlight key developments over the past year
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.
FROM RWCS 2021
No benefit seen with everolimus in early breast cancer
At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.
These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.
The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.
“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.
“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.
She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.
Study details
The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.
The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.
The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.
Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.
“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.
Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.
Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.
The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:
- Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
- Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
- Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).
With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
Problems interpreting data
There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.
For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.
In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.
Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.
Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.
Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.
With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.
“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”
Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”
Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”
Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.
The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.
At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.
These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.
The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.
“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.
“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.
She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.
Study details
The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.
The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.
The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.
Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.
“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.
Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.
Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.
The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:
- Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
- Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
- Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).
With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
Problems interpreting data
There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.
For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.
In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.
Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.
Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.
Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.
With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.
“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”
Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”
Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”
Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.
The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.
At a median follow-up of almost 3 years, rates of disease-free survival, distant metastasis-free survival, and overall survival were similar in the everolimus and hormone therapy-alone arms.
These findings were presented at the inaugural ESMO Virtual Plenary and published in Annals of Oncology.
The UNIRAD results contrast results from prior studies of everolimus in the advanced breast cancer setting. In the BOLERO-2 and BOLERO-4 studies, the mTOR inhibitor provided a progression-free survival benefit when added to hormone therapy.
“There clearly is rationale for targeted therapy in early ER+, HER2- breast cancer,” said Rebecca Dent, MD, of the National Cancer Center in Singapore, who chaired the ESMO Virtual Plenary in which the UNIRAD findings were presented.
“Patients with high-risk luminal breast cancer clearly have an unmet need. We probably still underestimate the risk of early and late recurrences, and chemotherapy is not necessarily the answer,” Dr. Dent said.
She observed that a lot has been learned about the mTOR pathway, including how complicated it is and its role in endocrine resistance. Since mTOR inhibition was standard care in the metastatic setting, “it really is appropriate now to test in early breast cancer,” she added.
Study details
The aim of the UNIRAD study was to compare the efficacy and safety of everolimus plus standard adjuvant hormone therapy to hormone therapy alone in women with ER+, HER2- early breast cancer who had a high risk of recurrence. High risk was defined as having more than four positive nodes, having one or more positive nodes after neoadjuvant chemotherapy or hormone therapy, or having one or more positive nodes and an EPclin score of 3.3 or higher.
The trial enrolled 1,278 patients. At baseline, their median age was 54 years (range, 48-63), 65.8% were postmenopausal, and 52.7% had four or more positive nodes.
The patients were randomized 1:1 to receive 2 years of everolimus plus hormone therapy or placebo plus hormone therapy. The type of hormone therapy was investigor’s choice.
Investigator Thomas Bachelot, MD, PhD, of Centre Leon Berard in Lyon, France, noted that the study started in 2013 and underwent several protocol amendments, first for accrual problems and then because of toxicity. This led to dropping the starting dose of everolimus from 10 mg to 5 mg.
“Acceptability was a concern; 50% of our patients stopped everolimus before study completion for toxicity or personal decision,” Dr. Bachelot acknowledged.
Grade 3 or higher adverse events were more frequent in patients taking everolimus (29.9%) than placebo (15.9%) in combination with hormone therapy. The rates of serious adverse events were a respective 11.8% and 9.3%.
Mucositis was one of the main adverse events, occurring in more than half of all patients treated with everolimus (33.8% grade 1, 25.4% grade 2, and 7.4% grade 3/4). The success of managing this side effect with a dexamethasone mouthwash was not known at the time of the UNIRAD trial design.
The study also showed no benefit of everolimus over placebo for the following efficacy outcomes:
- Disease-free survival – 88% and 89%, respectively (hazard ratio, 0.95; 95% confidence interval, 0.69-1.32; P = .78)
- Distant metastasis-free survival – 91% and 90%, respectively (HR, 0.88; 95% CI, 0.62-1.25)
- Overall survival – both 96% (HR, 1.09; 95% CI, 0.62-1.92).
With the exception of patients who had received tamoxifen rather than an aromatase inhibitor, a preplanned subgroup analysis suggested there was no population of patients who benefited from the addition of everolimus.
Problems interpreting data
There are several problems in interpreting the UNIRAD data, observed study discussant Peter Schmid, MD, PhD, of St. Bartholomew’s Hospital & Barts Cancer Institute in London.
For one, “whether we like it or not,” the trial was underpowered, he said. This was because the trial had been halted early for futility at the first interim analysis when about two-thirds of the intended study cohort had been accrued.
In addition, Dr. Schmid said, this is clearly not a trial that included patients with primary endocrine resistance. In all, 43% of patients had received less than 1 year of endocrine treatment, 42% had received 2-3 years, and 15% had received more than 3 years of endocrine treatment.
Dr. Schmid said that the starting dose of everolimus had to be lowered because of toxicity or poor acceptance. “As a result, two-thirds of patients received a 5-mg dose, and we don’t know whether that had an impact on efficacy,” he said.
Furthermore, the median time on treatment was less than half of what was initially planned, and 53% of patients had to stop everolimus before the end of the study.
Dr. Schmid noted that this discontinuation rate is higher than that seen in trials of CDK4/6 inhibitors added to endocrine treatment. Dropout rates were 19% in the negative Penelope-B trial with palbociclib, 42% in the negative PALLAS trial with palbociclib, and 27% in the positive monarchE trial with abemaciclib.
With such a high discontinuation rate in the UNIRAD trial, “we’re not sure whether we can ultimately evaluate really whether this trial did work,” Dr. Schmid said.
“Could the results change over time?” he asked. “I personally think it is unlikely, as the trial clearly has already an adequate follow-up for what it was supposed to show.”
Looking at whether the trial’s hypothesis is still valid, he added: “I think that is unclear to all of us, and we need to work out whether these compounds are cytostatic in nature, or cytotoxic. And that is something we need to learn over time.”
Commending the study overall, Dr. Schmid observed: “I think it was an excellent trial design based on what we knew at that time,” and the design “was changed in a pragmatic way because of recruitment challenges.”
Something for the future would be to select patients for such trials based on the tumor biology rather than risk status, Dr. Schmid suggested. “That is something we may have to take into consideration with our increasing knowledge around primary and secondary resistance and what treatments we want to introduce to target-resistant clones,” he said.
The UNIRAD study was sponsored by UNICANCER, with funding and support from the French Ministry of Health, Cancer Research UK, Myriad Genetics (which provided Endopredict tests), and Novartis (which provided everolimus and placebo). Dr. Bachelot, Dr. Schmid, and Dr. Dent disclosed relationships with Novartis and several other pharmaceutical companies.
FROM ESMO VIRTUAL PLENARY
Severe atopic dermatitis often puts a dent in quality of life
In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.
“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”
In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).
In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
Behavioral, neurocognitive effects
In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.
In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.
In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).
“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
Impact on depression, anxiety
Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).
“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”
The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).
“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”
Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.
“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).
“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”
Dr. Bender reported having no financial disclosures.
In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.
“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”
In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).
In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
Behavioral, neurocognitive effects
In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.
In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.
In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).
“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
Impact on depression, anxiety
Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).
“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”
The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).
“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”
Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.
“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).
“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”
Dr. Bender reported having no financial disclosures.
In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.
“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”
In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).
In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
Behavioral, neurocognitive effects
In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.
In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.
In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).
“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
Impact on depression, anxiety
Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).
“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”
The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).
“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”
Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.
“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).
“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”
Dr. Bender reported having no financial disclosures.
FROM REVOLUTIONIZING AD 2020
NfL levels linked to worse disability in real-world MS
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new findings from a large, diverse population of patients with MS. “This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” said lead author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore.
“An important strength of this cohort is that it is a real-world cohort of patients followed in U.S. and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”
The research was presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Scrutinizing serum neurofilament light chain levels in a real-world cohort
Neurofilaments – neuron-specific proteins that release in response to neuroaxonal injury – have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But studies involving real-world, heterogeneous MS populations are lacking, the researchers noted.
To take a broader look at the issue, Dr. Sotirchos and colleagues conducted a cross-sectional evaluation of 6,968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.
Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high-throughput immunoassay (Siemens Healthineers).
Of those with MS, 1,202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.
A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio, 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs. never smoker; OR, 1.49).
Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.
Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).
Evaluation of neuroperformance measures – including walking speed, manual dexterity and processing speed, and MRI data – showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).
Dr. Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity. “Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated serum neurofilament light chain levels.”
The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Dr. Sotirchos added. “Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain levels is distributed in the body,” he explained.
The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Dr. Sotirchos noted. “It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”
Dr. Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.
“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.” In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.
Applying the findings to individual patients
Commenting on the findings, Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.
“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she said.
“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cutoffs for what’s abnormal can be created,” said Dr. Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.
Dr. Graves noted that the findings on BMI were unexpected. “Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.
“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added.
Future research
In terms of future directions, Dr. Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.
The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.
“It appears that reference ranges may need to account for sex, race, BMI, and comorbid/lifestyle factors,” Dr. Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”
The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Dr. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio, and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Dr. Graves has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS 2021
Earlier antibiotic initiation for sepsis did not lead to overuse
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
FROM CCC50
Vitamin D deficiency linked to early cognitive impairment in MS
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to new research that adds to the known adverse relationship between low vitamin D and MS.
“We confirmed that low vitamin D may affect not only early disability but also cognition in newly MS diagnosed patients,” said lead author Eleonora Virgilio, MD, of the MS Center, neurology unit, at the University of Eastern Piedmont, Novara, Italy.
“The possible effects of vitamin D on both cognition (in particular, information processing speed) and early disability in newly diagnosed MS patients needs to be further investigated because this association might represent a marker of future disability, supporting the need for prompt supplementation,” she said.
The findings were presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Low vitamin D and MS
Previous studies have linked insufficient serum vitamin D with everything from the development of MS to activity and disease progression, but less has been reported on a specific link to the impairment of cognitive function, an important complication of MS.
“Cognitive impairment, and, in particular, slowed information processing speed, is very frequent in the MS population from the early stages of disease, and frequently underestimated,” Dr. Virgilio noted. “It has yet to be completely elucidated what the exact underlying mechanisms are.”
To evaluate the relationship, Dr. Virgilio and colleagues enrolled 60 patients in Italy with MS who were newly diagnosed and had serum vitamin D levels collected upon diagnosis. The participants were also tested at diagnosis with the Symbol Digit Modalities Test (SDMT) for information processing speed, which is a hallmark of the cognitive impairment that can occur in MS and is typically the first cognitive domain to show effects of the disease.
Among the patients, 40 were female and the mean age at diagnosis was 39.5 years; 90% had relapsing remitting MS at baseline and 10% had progressive MS. Their median Expanded Disability Status Scale score at diagnosis was 1.5.
At baseline, as many as 85% of the participants (51) had low serum vitamin D levels, defined as below 30 ng/mL, which Dr. Virgilio noted is consistent with other rates reported among people with MS in the Lombardy region of Italy, where the study was conducted.
The patients had a mean vitamin D level of 21.17 ng/mL (± 10.02), with 51.7% considered to have a deficiency (less than 20 ng/mL) and 33.3% with an insufficiency (20-30 ng/mL).
Of the patients, 16 (27%) had cognitive impairment, defined as a z score of 1.5 or less. Their mean raw SDMT score was 46.50 (± 14.73) and mean z score was –0.62 (± 1.29).
Importantly, those with cognitive impairment were significantly more likely to have severe hypovitaminosis D, compared with those with sufficient vitamin D levels, none of whom showed cognitive impairment (P = .02).
Furthermore, vitamin D levels positively correlated with SDMT raw values (P = .001) and z score (P = .008).
Over a mean follow-up of 2 years, a significant correlation was observed between serum vitamin D levels at diagnosis and early disability on the MS severity score (MSSS; P = .02) and a weak correlation with age-related MSSS (ARMSS; P = .08) at the last clinical follow-up.
Dr. Virgilio noted that factors including disease treatment effects or other factors could have played a role in the weaker results. “It is possible that the linear correlation we found was not as strong as expected [because of] an effect of treatment with disease-modifying therapies or vitamin D supplementation, or because of the short follow-up available at the moment for our population – only for a mean period of 2 years after MS diagnosis.”
The mechanisms for vitamin D deficiency in the MS population are likely multifactorial, with genetic as well as environmental links, she noted.
“The immunomodulatory effects of vitamin D are well known,” Dr. Virgilio said.
“Vitamin D was already linked to cognitive function in other neurodegenerative diseases, [including] Alzheimer’s disease, but more importantly, also in other autoimmune diseases, such as systemic lupus erythematosus,” she explained.
Vitamin D also linked to long-term cognitive function
The study adds to recent research showing longer-term effects of vitamin D deficiency and cognitive impairment in MS: In the longitudinal BENEFIT trial published in 2020, researchers following 278 patients with MS over the course of 11 years found that a 50 ng/L higher mean vitamin D level in the first 2 years of the study was associated with a 65% lower odds of a poor performance on Paced Auditory Serial Addition Test scores at the 11-year follow-up.
That study also looked at neurofilament light chain concentrations, which are associated with MS disease activity, and found they were 20% lower among those with higher vitamin D at baseline. Smokers also had lower cognitive scores.
“Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS,” the authors concluded.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021
When should a patient’s violent thoughts trigger your action?
When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
Dr. Ferranti reported having no disclosures.
When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
Dr. Ferranti reported having no disclosures.
When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
Dr. Ferranti reported having no disclosures.
FROM NPA 2021
Novel agent shows promise against cat allergy
One dose of the novel agent, REGN1908-1909 (Regeneron Pharmaceuticals) resulted in a rapid and durable reduction in cat-allergen-induced bronchoconstriction in cat-allergic subjects with mild asthma.
The finding, from a phase 2 randomized placebo-controlled study, is good news for the millions of people who are plagued by cat allergies, the investigators say.
The study, which was sponsored by Regeneron, was presented in a late breaking oral abstract session at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“REGN1908-1909 contains antibodies against Fel d 1, the major cat allergen, and here we show that it quickly and lastingly reduces acute bronchoconstriction in people with cat allergy,” lead author Frederic J. de Blay, MD, Strasbourg University Hospital, France, said in an interview.
Dr. de Blay admitted he is “quite excited” about the results.
“This study was performed in an environmental exposure chamber, and we clearly demonstrate that these antibodies decrease the asthmatic response to cat allergen within 8 days, and that these effects last 3 months. I never saw that in my life. I was a little bit skeptical at first, so to obtain such robust results after just 8 days, after just one injection, I was very surprised,” he said.
Dr. de Blay and his team screened potential participants to make sure they were cat allergic by exposing them to cat allergen for up to 2 hours while they were in the environmental exposure chamber. To be eligible for the study, participants had to show an early asthmatic response (EAR), defined as a reduction in forced expiratory volume in 1 second (FEV1) of at least 20% from baseline.
The participants were then randomized to receive either single-dose REGN1908-1909, 600 mg, subcutaneously (n = 29 patients) or placebo (n = 27 patients) prior to cat-allergen exposure in the controlled environmental chamber.
Dr. de Blay developed the chamber used in the study: the ALYATEC environmental exposure chamber.
“The chamber is 60 meters square, or 150 cubic meters, and can accommodate 20 patients. We are able to nebulize cat allergen, mice allergen, or whatever we wish to study so we can standardize the exposure. We can control the particle size and the amount so we know the exact amount of allergen that the patient has been exposed to,” he explained.
To test the efficacy of REGN1908-1909 in reducing acute bronchoconstriction, or EAR, the researchers measured FEV1 at baseline, and on days 8, 29, 57, and 85 in both groups. During each exposure, measurements were taken every 10 minutes for periods that lasted up to 4 hours.
They found that the probability of remaining in the chamber with no asthmatic response was substantially elevated in the group treated with REGN1908-1909.
Compared with placebo, REGN1908-1909 significantly increased the median time to EAR, from 51 minutes at baseline to more than 4 hours on day 8, (hazard ratio [HR], 0.36; P < .0083), day 29 (HR, 0.24; P < .0001), day 57 (HR, 0.45; P = .0222), and day 85 (HR, 0.27; P = .0003).
The FEV1 area under the curve (AUC) was also better with REGN1908-1909 than with placebo at day 8 (15.2% vs. 1.6%; P < .001). And a single dose reduced skin-test reactivity to cat allergen at 1 week, which persisted for up to 4 months.
In addition, participants who received REGN1908-1909 were able to tolerate a threefold higher amount of the cat allergen than those who received placebo (P = .003).
“We initially gave 40 nanograms of cat allergen, and then 8 days later they were able to stay longer in the chamber and inhale more of the allergen, to almost triple the amount they had originally been given. That 40 nanograms is very close to real world exposure,” Dr. de Blay noted.
Regeneron plans to start a phase 3 trial soon, he reported.
Promising results
“The study is well designed and shows a reduction in drop of FEV1 in response to cat allergen provocation and a decreased AUC in cat SPT response over 4 months,” Jonathan A. Bernstein, MD, professor of medicine at the University of Cincinnati, said in an interview.
“These are very promising results, which show that REGN1908-1909 can be a novel treatment for cat-induced asthma, which is often the only sensitization patients have. And they love their cats – one-third of the U.S. population has a cat and one-third has a dog, and 50% have both,” noted Dr. Bernstein, who was not involved with the study.
“This novel study used our scientific knowledge of the cat allergen itself to design a targeted antibody-based treatment that demonstrates significant benefit even after the first shot,” added Edwin H. Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill.
“This strategy has the potential to revolutionize not only our treatment of common environmental allergies but also other allergic diseases with well-described triggers, such as food and drug allergy,” Dr. Kim, who was not part of the study, said in an interview.
Dr. de Blay reported a financial relationship with Regeneron Pharmaceuticals, which sponsored the study. Dr. Bernstein and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
One dose of the novel agent, REGN1908-1909 (Regeneron Pharmaceuticals) resulted in a rapid and durable reduction in cat-allergen-induced bronchoconstriction in cat-allergic subjects with mild asthma.
The finding, from a phase 2 randomized placebo-controlled study, is good news for the millions of people who are plagued by cat allergies, the investigators say.
The study, which was sponsored by Regeneron, was presented in a late breaking oral abstract session at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“REGN1908-1909 contains antibodies against Fel d 1, the major cat allergen, and here we show that it quickly and lastingly reduces acute bronchoconstriction in people with cat allergy,” lead author Frederic J. de Blay, MD, Strasbourg University Hospital, France, said in an interview.
Dr. de Blay admitted he is “quite excited” about the results.
“This study was performed in an environmental exposure chamber, and we clearly demonstrate that these antibodies decrease the asthmatic response to cat allergen within 8 days, and that these effects last 3 months. I never saw that in my life. I was a little bit skeptical at first, so to obtain such robust results after just 8 days, after just one injection, I was very surprised,” he said.
Dr. de Blay and his team screened potential participants to make sure they were cat allergic by exposing them to cat allergen for up to 2 hours while they were in the environmental exposure chamber. To be eligible for the study, participants had to show an early asthmatic response (EAR), defined as a reduction in forced expiratory volume in 1 second (FEV1) of at least 20% from baseline.
The participants were then randomized to receive either single-dose REGN1908-1909, 600 mg, subcutaneously (n = 29 patients) or placebo (n = 27 patients) prior to cat-allergen exposure in the controlled environmental chamber.
Dr. de Blay developed the chamber used in the study: the ALYATEC environmental exposure chamber.
“The chamber is 60 meters square, or 150 cubic meters, and can accommodate 20 patients. We are able to nebulize cat allergen, mice allergen, or whatever we wish to study so we can standardize the exposure. We can control the particle size and the amount so we know the exact amount of allergen that the patient has been exposed to,” he explained.
To test the efficacy of REGN1908-1909 in reducing acute bronchoconstriction, or EAR, the researchers measured FEV1 at baseline, and on days 8, 29, 57, and 85 in both groups. During each exposure, measurements were taken every 10 minutes for periods that lasted up to 4 hours.
They found that the probability of remaining in the chamber with no asthmatic response was substantially elevated in the group treated with REGN1908-1909.
Compared with placebo, REGN1908-1909 significantly increased the median time to EAR, from 51 minutes at baseline to more than 4 hours on day 8, (hazard ratio [HR], 0.36; P < .0083), day 29 (HR, 0.24; P < .0001), day 57 (HR, 0.45; P = .0222), and day 85 (HR, 0.27; P = .0003).
The FEV1 area under the curve (AUC) was also better with REGN1908-1909 than with placebo at day 8 (15.2% vs. 1.6%; P < .001). And a single dose reduced skin-test reactivity to cat allergen at 1 week, which persisted for up to 4 months.
In addition, participants who received REGN1908-1909 were able to tolerate a threefold higher amount of the cat allergen than those who received placebo (P = .003).
“We initially gave 40 nanograms of cat allergen, and then 8 days later they were able to stay longer in the chamber and inhale more of the allergen, to almost triple the amount they had originally been given. That 40 nanograms is very close to real world exposure,” Dr. de Blay noted.
Regeneron plans to start a phase 3 trial soon, he reported.
Promising results
“The study is well designed and shows a reduction in drop of FEV1 in response to cat allergen provocation and a decreased AUC in cat SPT response over 4 months,” Jonathan A. Bernstein, MD, professor of medicine at the University of Cincinnati, said in an interview.
“These are very promising results, which show that REGN1908-1909 can be a novel treatment for cat-induced asthma, which is often the only sensitization patients have. And they love their cats – one-third of the U.S. population has a cat and one-third has a dog, and 50% have both,” noted Dr. Bernstein, who was not involved with the study.
“This novel study used our scientific knowledge of the cat allergen itself to design a targeted antibody-based treatment that demonstrates significant benefit even after the first shot,” added Edwin H. Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill.
“This strategy has the potential to revolutionize not only our treatment of common environmental allergies but also other allergic diseases with well-described triggers, such as food and drug allergy,” Dr. Kim, who was not part of the study, said in an interview.
Dr. de Blay reported a financial relationship with Regeneron Pharmaceuticals, which sponsored the study. Dr. Bernstein and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
One dose of the novel agent, REGN1908-1909 (Regeneron Pharmaceuticals) resulted in a rapid and durable reduction in cat-allergen-induced bronchoconstriction in cat-allergic subjects with mild asthma.
The finding, from a phase 2 randomized placebo-controlled study, is good news for the millions of people who are plagued by cat allergies, the investigators say.
The study, which was sponsored by Regeneron, was presented in a late breaking oral abstract session at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“REGN1908-1909 contains antibodies against Fel d 1, the major cat allergen, and here we show that it quickly and lastingly reduces acute bronchoconstriction in people with cat allergy,” lead author Frederic J. de Blay, MD, Strasbourg University Hospital, France, said in an interview.
Dr. de Blay admitted he is “quite excited” about the results.
“This study was performed in an environmental exposure chamber, and we clearly demonstrate that these antibodies decrease the asthmatic response to cat allergen within 8 days, and that these effects last 3 months. I never saw that in my life. I was a little bit skeptical at first, so to obtain such robust results after just 8 days, after just one injection, I was very surprised,” he said.
Dr. de Blay and his team screened potential participants to make sure they were cat allergic by exposing them to cat allergen for up to 2 hours while they were in the environmental exposure chamber. To be eligible for the study, participants had to show an early asthmatic response (EAR), defined as a reduction in forced expiratory volume in 1 second (FEV1) of at least 20% from baseline.
The participants were then randomized to receive either single-dose REGN1908-1909, 600 mg, subcutaneously (n = 29 patients) or placebo (n = 27 patients) prior to cat-allergen exposure in the controlled environmental chamber.
Dr. de Blay developed the chamber used in the study: the ALYATEC environmental exposure chamber.
“The chamber is 60 meters square, or 150 cubic meters, and can accommodate 20 patients. We are able to nebulize cat allergen, mice allergen, or whatever we wish to study so we can standardize the exposure. We can control the particle size and the amount so we know the exact amount of allergen that the patient has been exposed to,” he explained.
To test the efficacy of REGN1908-1909 in reducing acute bronchoconstriction, or EAR, the researchers measured FEV1 at baseline, and on days 8, 29, 57, and 85 in both groups. During each exposure, measurements were taken every 10 minutes for periods that lasted up to 4 hours.
They found that the probability of remaining in the chamber with no asthmatic response was substantially elevated in the group treated with REGN1908-1909.
Compared with placebo, REGN1908-1909 significantly increased the median time to EAR, from 51 minutes at baseline to more than 4 hours on day 8, (hazard ratio [HR], 0.36; P < .0083), day 29 (HR, 0.24; P < .0001), day 57 (HR, 0.45; P = .0222), and day 85 (HR, 0.27; P = .0003).
The FEV1 area under the curve (AUC) was also better with REGN1908-1909 than with placebo at day 8 (15.2% vs. 1.6%; P < .001). And a single dose reduced skin-test reactivity to cat allergen at 1 week, which persisted for up to 4 months.
In addition, participants who received REGN1908-1909 were able to tolerate a threefold higher amount of the cat allergen than those who received placebo (P = .003).
“We initially gave 40 nanograms of cat allergen, and then 8 days later they were able to stay longer in the chamber and inhale more of the allergen, to almost triple the amount they had originally been given. That 40 nanograms is very close to real world exposure,” Dr. de Blay noted.
Regeneron plans to start a phase 3 trial soon, he reported.
Promising results
“The study is well designed and shows a reduction in drop of FEV1 in response to cat allergen provocation and a decreased AUC in cat SPT response over 4 months,” Jonathan A. Bernstein, MD, professor of medicine at the University of Cincinnati, said in an interview.
“These are very promising results, which show that REGN1908-1909 can be a novel treatment for cat-induced asthma, which is often the only sensitization patients have. And they love their cats – one-third of the U.S. population has a cat and one-third has a dog, and 50% have both,” noted Dr. Bernstein, who was not involved with the study.
“This novel study used our scientific knowledge of the cat allergen itself to design a targeted antibody-based treatment that demonstrates significant benefit even after the first shot,” added Edwin H. Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill.
“This strategy has the potential to revolutionize not only our treatment of common environmental allergies but also other allergic diseases with well-described triggers, such as food and drug allergy,” Dr. Kim, who was not part of the study, said in an interview.
Dr. de Blay reported a financial relationship with Regeneron Pharmaceuticals, which sponsored the study. Dr. Bernstein and Dr. Kim have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAAAI
Mepolizumab reduced exacerbations in patients with asthma and atopy, depression comorbidities
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
FROM AAAAI 2021