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Abatacept response in seropositive RA may be linked to HLA gene
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
REPORTING FROM THE EULAR 2019 Congress
Living small
I’m sitting on the porch looking out at our little harbor, listening to the murmurings of the family of renters who have just moved into the cottage next door. We are on the cusp of the tourist season that draws millions of visitors – more than 36 million in 2017 – to a state that has less than a million and a half year-round residents during the other 9 months. Why do the “people from away” come?
The water is too cold for swimming most of the summer in Maine. But we have forested mountains, rocky shores, and we’re small. When I chat with the visitors sharing our stony little beach, they often ask if I live here and tell me how lucky I am because they envy the quiet, the friendly people, the lack of traffic, and the sense of community that they feel here in Vacationland.
My being here in Maine wasn’t a stroke of luck. It was a conscious decision that my wife and I made when I finished my training. The lucky part was meeting my wife who was born here. Through her I learned what Maine was about. I had grown up in a small town of 5,000 (although it was the suburb of a city of millions) and went to a small college in rural New Hampshire with an enrollment of a little more than 3,000. I turned down residencies in pediatric radiology and dermatology because I knew that to have a sustainable patient base we would have needed to live in a major metropolitan center.
I was accustomed to the benefits of living small. In the 1970s, the local economy in mid-coast Maine was shaky, the biggest employer had not yet secured the large military contracts it needed to thrive. But we decided it was a risk worth taking, and we have never regretted for a second living and practicing in a town of less than 20,000.
With this history as a backdrop, you can understand why I am a bit puzzled and disappointed by the results of a 2019 survey final-year medical residents recently published by the medical search and consulting firm Merritt Hawkins. Although the sample size is small (391 respondents out of 20,000 email surveys), the responses probably are a reasonable reflection of the opinions of the entire population of final-year residents. More than 80% of the respondents said that they would most like to practice in a community with a population of more than 100,000, and 65% would prefer a population base of more than 250,000. This would automatically rule out Maine, where our largest city has less than 80,000 people.
I can easily understand why physicians finishing their residency would avoid practice opportunities in remote, thinly populated regions in which they might find themselves as the only, or one of only two physicians serving a medically needy, economically depressed population spread out over a wide geographic area. That kind of challenge has some appeal for the saintly few, or the dreamy-eyed idealists. But in my experience, those work environments require so much energy that most physicians last only a few years because being on call is so taxing.
However, I know of several right here in Maine. What is driving young physicians to seek larger communities? It may be that because teaching hospitals are usually in more densely populated communities, many residents lack sufficient exposure to role models who are practicing in smaller settings. Compounding this dearth of role models is the unfortunate and often inaccurate image in which local doctors are cast as bumbling and clueless. I was fortunate because where I did my first 2 years of training, the local pediatricians played an active role and were very visible role models of how one can enjoy practice in a smaller community.
I guess I can’t ignore the obvious that a larger population base may be able guarantee an income that could sound appealing to the more than 50% of residents who will complete their training with a sizable debt.
However, I fear that too many residents nearing the end of their training believe that the “quality of life” that they claim to be seeking can’t be found in a small community practice. They would do well to speak to a few of us who have enjoyed and prospered by living small.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
I’m sitting on the porch looking out at our little harbor, listening to the murmurings of the family of renters who have just moved into the cottage next door. We are on the cusp of the tourist season that draws millions of visitors – more than 36 million in 2017 – to a state that has less than a million and a half year-round residents during the other 9 months. Why do the “people from away” come?
The water is too cold for swimming most of the summer in Maine. But we have forested mountains, rocky shores, and we’re small. When I chat with the visitors sharing our stony little beach, they often ask if I live here and tell me how lucky I am because they envy the quiet, the friendly people, the lack of traffic, and the sense of community that they feel here in Vacationland.
My being here in Maine wasn’t a stroke of luck. It was a conscious decision that my wife and I made when I finished my training. The lucky part was meeting my wife who was born here. Through her I learned what Maine was about. I had grown up in a small town of 5,000 (although it was the suburb of a city of millions) and went to a small college in rural New Hampshire with an enrollment of a little more than 3,000. I turned down residencies in pediatric radiology and dermatology because I knew that to have a sustainable patient base we would have needed to live in a major metropolitan center.
I was accustomed to the benefits of living small. In the 1970s, the local economy in mid-coast Maine was shaky, the biggest employer had not yet secured the large military contracts it needed to thrive. But we decided it was a risk worth taking, and we have never regretted for a second living and practicing in a town of less than 20,000.
With this history as a backdrop, you can understand why I am a bit puzzled and disappointed by the results of a 2019 survey final-year medical residents recently published by the medical search and consulting firm Merritt Hawkins. Although the sample size is small (391 respondents out of 20,000 email surveys), the responses probably are a reasonable reflection of the opinions of the entire population of final-year residents. More than 80% of the respondents said that they would most like to practice in a community with a population of more than 100,000, and 65% would prefer a population base of more than 250,000. This would automatically rule out Maine, where our largest city has less than 80,000 people.
I can easily understand why physicians finishing their residency would avoid practice opportunities in remote, thinly populated regions in which they might find themselves as the only, or one of only two physicians serving a medically needy, economically depressed population spread out over a wide geographic area. That kind of challenge has some appeal for the saintly few, or the dreamy-eyed idealists. But in my experience, those work environments require so much energy that most physicians last only a few years because being on call is so taxing.
However, I know of several right here in Maine. What is driving young physicians to seek larger communities? It may be that because teaching hospitals are usually in more densely populated communities, many residents lack sufficient exposure to role models who are practicing in smaller settings. Compounding this dearth of role models is the unfortunate and often inaccurate image in which local doctors are cast as bumbling and clueless. I was fortunate because where I did my first 2 years of training, the local pediatricians played an active role and were very visible role models of how one can enjoy practice in a smaller community.
I guess I can’t ignore the obvious that a larger population base may be able guarantee an income that could sound appealing to the more than 50% of residents who will complete their training with a sizable debt.
However, I fear that too many residents nearing the end of their training believe that the “quality of life” that they claim to be seeking can’t be found in a small community practice. They would do well to speak to a few of us who have enjoyed and prospered by living small.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
I’m sitting on the porch looking out at our little harbor, listening to the murmurings of the family of renters who have just moved into the cottage next door. We are on the cusp of the tourist season that draws millions of visitors – more than 36 million in 2017 – to a state that has less than a million and a half year-round residents during the other 9 months. Why do the “people from away” come?
The water is too cold for swimming most of the summer in Maine. But we have forested mountains, rocky shores, and we’re small. When I chat with the visitors sharing our stony little beach, they often ask if I live here and tell me how lucky I am because they envy the quiet, the friendly people, the lack of traffic, and the sense of community that they feel here in Vacationland.
My being here in Maine wasn’t a stroke of luck. It was a conscious decision that my wife and I made when I finished my training. The lucky part was meeting my wife who was born here. Through her I learned what Maine was about. I had grown up in a small town of 5,000 (although it was the suburb of a city of millions) and went to a small college in rural New Hampshire with an enrollment of a little more than 3,000. I turned down residencies in pediatric radiology and dermatology because I knew that to have a sustainable patient base we would have needed to live in a major metropolitan center.
I was accustomed to the benefits of living small. In the 1970s, the local economy in mid-coast Maine was shaky, the biggest employer had not yet secured the large military contracts it needed to thrive. But we decided it was a risk worth taking, and we have never regretted for a second living and practicing in a town of less than 20,000.
With this history as a backdrop, you can understand why I am a bit puzzled and disappointed by the results of a 2019 survey final-year medical residents recently published by the medical search and consulting firm Merritt Hawkins. Although the sample size is small (391 respondents out of 20,000 email surveys), the responses probably are a reasonable reflection of the opinions of the entire population of final-year residents. More than 80% of the respondents said that they would most like to practice in a community with a population of more than 100,000, and 65% would prefer a population base of more than 250,000. This would automatically rule out Maine, where our largest city has less than 80,000 people.
I can easily understand why physicians finishing their residency would avoid practice opportunities in remote, thinly populated regions in which they might find themselves as the only, or one of only two physicians serving a medically needy, economically depressed population spread out over a wide geographic area. That kind of challenge has some appeal for the saintly few, or the dreamy-eyed idealists. But in my experience, those work environments require so much energy that most physicians last only a few years because being on call is so taxing.
However, I know of several right here in Maine. What is driving young physicians to seek larger communities? It may be that because teaching hospitals are usually in more densely populated communities, many residents lack sufficient exposure to role models who are practicing in smaller settings. Compounding this dearth of role models is the unfortunate and often inaccurate image in which local doctors are cast as bumbling and clueless. I was fortunate because where I did my first 2 years of training, the local pediatricians played an active role and were very visible role models of how one can enjoy practice in a smaller community.
I guess I can’t ignore the obvious that a larger population base may be able guarantee an income that could sound appealing to the more than 50% of residents who will complete their training with a sizable debt.
However, I fear that too many residents nearing the end of their training believe that the “quality of life” that they claim to be seeking can’t be found in a small community practice. They would do well to speak to a few of us who have enjoyed and prospered by living small.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Recognize and assess RA fatigue routinely, rheumatology experts urge
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
REPORTING FROM EULAR 2019 CONGRESS
Collagen powder deemed noninferior to primary closure for punch-biopsy healing
Collagen powder may be noninferior to primary closure for healing punch biopsy–induced wounds and possibly leads to improved early cosmetic outcomes and accelerated wound maturation, according to Azam Qureshi of the University of Maryland, Baltimore, and associates.
In a small pilot study published in Journal of Drugs in Dermatology, eight volunteers (mean age, 37 years) received a 4-mm punch biopsy on each thigh. One wound was managed with primary closure, the other with daily application of collagen powder. The wounds were biopsied at 4 weeks for histopathologic analysis, and the study subjects rated pain, itch, and treatment preferences at 1, 2, 4, 6, and 12 weeks.
The size of wounds treated with collagen was reduced by 28.95% at 1 week, 55.76% at 2 weeks, and 95.94% at 4 weeks; six of the eight collagen-treated wounds were completely healed at 4 weeks. Wound size was reduced by 75.71% 1 week after the second biopsy, much faster than the initial healing. In addition to collagen, one patient required hyfrecation for hemostasis, which did not affect results; three of the eight subjects rated the collagen treatment as “annoying,” but no one rated it as “difficult,” and patients generally regarded collagen treatment as more time consuming.
The histopathologic analysis showed epidermal reepithelialization in collagen-treated wounds and wounds managed with primary closure, with more organized granulation tissue in the collagen-treated wounds. Similar pain and itch ratings were reported between wound types, and both patients and blinded dermatologists observing the study preferred the appearance of collagen-treated wounds.
“Future research elucidating the optimal duration of collagen therapy is needed, as less than 4 weeks may be sufficient. Shortened treatment courses would decrease the cost and effort required by patients. Future studies should also investigate the efficacy of collagen powder in healing larger wounds and in comparison to healing by secondary intention,” the investigators wrote.
CPN Biosciences funded the study. No authors had relevant financial disclosures.
SOURCE: Qureshi A et al. J Drug Dermatol. 2019;18(7):667-73
Collagen powder may be noninferior to primary closure for healing punch biopsy–induced wounds and possibly leads to improved early cosmetic outcomes and accelerated wound maturation, according to Azam Qureshi of the University of Maryland, Baltimore, and associates.
In a small pilot study published in Journal of Drugs in Dermatology, eight volunteers (mean age, 37 years) received a 4-mm punch biopsy on each thigh. One wound was managed with primary closure, the other with daily application of collagen powder. The wounds were biopsied at 4 weeks for histopathologic analysis, and the study subjects rated pain, itch, and treatment preferences at 1, 2, 4, 6, and 12 weeks.
The size of wounds treated with collagen was reduced by 28.95% at 1 week, 55.76% at 2 weeks, and 95.94% at 4 weeks; six of the eight collagen-treated wounds were completely healed at 4 weeks. Wound size was reduced by 75.71% 1 week after the second biopsy, much faster than the initial healing. In addition to collagen, one patient required hyfrecation for hemostasis, which did not affect results; three of the eight subjects rated the collagen treatment as “annoying,” but no one rated it as “difficult,” and patients generally regarded collagen treatment as more time consuming.
The histopathologic analysis showed epidermal reepithelialization in collagen-treated wounds and wounds managed with primary closure, with more organized granulation tissue in the collagen-treated wounds. Similar pain and itch ratings were reported between wound types, and both patients and blinded dermatologists observing the study preferred the appearance of collagen-treated wounds.
“Future research elucidating the optimal duration of collagen therapy is needed, as less than 4 weeks may be sufficient. Shortened treatment courses would decrease the cost and effort required by patients. Future studies should also investigate the efficacy of collagen powder in healing larger wounds and in comparison to healing by secondary intention,” the investigators wrote.
CPN Biosciences funded the study. No authors had relevant financial disclosures.
SOURCE: Qureshi A et al. J Drug Dermatol. 2019;18(7):667-73
Collagen powder may be noninferior to primary closure for healing punch biopsy–induced wounds and possibly leads to improved early cosmetic outcomes and accelerated wound maturation, according to Azam Qureshi of the University of Maryland, Baltimore, and associates.
In a small pilot study published in Journal of Drugs in Dermatology, eight volunteers (mean age, 37 years) received a 4-mm punch biopsy on each thigh. One wound was managed with primary closure, the other with daily application of collagen powder. The wounds were biopsied at 4 weeks for histopathologic analysis, and the study subjects rated pain, itch, and treatment preferences at 1, 2, 4, 6, and 12 weeks.
The size of wounds treated with collagen was reduced by 28.95% at 1 week, 55.76% at 2 weeks, and 95.94% at 4 weeks; six of the eight collagen-treated wounds were completely healed at 4 weeks. Wound size was reduced by 75.71% 1 week after the second biopsy, much faster than the initial healing. In addition to collagen, one patient required hyfrecation for hemostasis, which did not affect results; three of the eight subjects rated the collagen treatment as “annoying,” but no one rated it as “difficult,” and patients generally regarded collagen treatment as more time consuming.
The histopathologic analysis showed epidermal reepithelialization in collagen-treated wounds and wounds managed with primary closure, with more organized granulation tissue in the collagen-treated wounds. Similar pain and itch ratings were reported between wound types, and both patients and blinded dermatologists observing the study preferred the appearance of collagen-treated wounds.
“Future research elucidating the optimal duration of collagen therapy is needed, as less than 4 weeks may be sufficient. Shortened treatment courses would decrease the cost and effort required by patients. Future studies should also investigate the efficacy of collagen powder in healing larger wounds and in comparison to healing by secondary intention,” the investigators wrote.
CPN Biosciences funded the study. No authors had relevant financial disclosures.
SOURCE: Qureshi A et al. J Drug Dermatol. 2019;18(7):667-73
FROM JOURNAL OF DRUGS IN DERMATOLOGY
After prior TNFi in axSpA, taking secukinumab or another TNFi appear equivalent
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
REPORTING FROM EULAR 2019 CONGRESS
CDC Advisory: Acute Flaccid Myelitis
Late summer is the season to be especially alert for possible cases of acute flaccid myelitis (AFM), the CDC says.
Since 2014, when the CDC began tracking AFM, 570 cases, mostly in children, have been reported. Outbreaks have followed a pattern: every 2 years, spiking between August and October. Nearly all states and DC have reported cases. The largest outbreak, 233 cases, was in 2018. Theoretically, 2019 would be an off year, but too little is known about AFM to say outbreaks are unlikely.
AFM starts with symptoms similar to those of a viral infection but can progress rapidly to limb weakness, then respiratory failure. Most patients are previously healthy children, average age 5 years old, who had respiratory symptoms or fever consistent with a viral infection less than a week before they experienced sudden weakness in their arms or legs. On average, the CDC receives reports of suspected AFM cases 18 days after the patient develops limb weakness.
The CDC believes viruses play a role, but which ones is still unclear. Symptoms have been found to develop after poliovirus, West Nile virus, and adenovirus infections. In an analysis of confirmed cases from 2018, CDC researchers detected enteroviruses and rhinoviruses in nearly half of stool and respiratory specimens. However, of 74 cases with a cerebral spinal fluid specimen, only 2 were positive for enteroviruses. All specimens tested negative for poliovirus.
But even when it is associated with a viral infection, it is not known how the infection triggered the AFM, or why it triggers AFM in some people and not others. AFM is rare—affecting ≤ 2 children per million in the US every year. Viral infections from enteroviruses are common, especially in children—and especially in the late summer/early autumn months. It is not known why a small number of people develop AFM while most others recover.
AFM can be difficult to diagnose because the symptoms are similar to those of neurologic diseases, such as Guillain-Barré syndrome. As of yet, no laboratory test is available; diagnosis is done through physical examination and magnetic resonance imaging (MRI) scans of the spinal cord.
There also are no proven ways to treat or prevent AFM. That is why timing is so key. The CDC says as soon as AFM is suspected, collect cerebral spinal fluid, serum, stool, and nasopharyngeal swabs. If an MRI shows a spinal lesion with some gray matter involvement, alert the health department and send specimens and medical records. Refer to specialists, monitor the patient for worsening symptoms, hospitalize if indicated, and begin treatment and rehabilitation.
In short: no specific etiology, no specific way to diagnose, and no specific treatment exist for AFM. Treatments, including immunoglobulin, corticosteroids, and antivirals have been tried, but no clear evidence exists that any have affected recovery. Other treatment is supportive, with physical and occupational therapy.
The length of recovery time varies. Some people make a full recovery, most have continued muscle weakness even after a year.
The CDC is researching possible risk factors, conducting advanced laboratory testing and research to determine how viral infections may lead to AFM, and tracking long-term patient outcomes.
Clinicians can contact neurologists who specialize in AFM through the AFM Physician Consult and Support Portal: https://myelitis.org/living-with-myelitis/resources/afm-physician-support-portal/.
Late summer is the season to be especially alert for possible cases of acute flaccid myelitis (AFM), the CDC says.
Since 2014, when the CDC began tracking AFM, 570 cases, mostly in children, have been reported. Outbreaks have followed a pattern: every 2 years, spiking between August and October. Nearly all states and DC have reported cases. The largest outbreak, 233 cases, was in 2018. Theoretically, 2019 would be an off year, but too little is known about AFM to say outbreaks are unlikely.
AFM starts with symptoms similar to those of a viral infection but can progress rapidly to limb weakness, then respiratory failure. Most patients are previously healthy children, average age 5 years old, who had respiratory symptoms or fever consistent with a viral infection less than a week before they experienced sudden weakness in their arms or legs. On average, the CDC receives reports of suspected AFM cases 18 days after the patient develops limb weakness.
The CDC believes viruses play a role, but which ones is still unclear. Symptoms have been found to develop after poliovirus, West Nile virus, and adenovirus infections. In an analysis of confirmed cases from 2018, CDC researchers detected enteroviruses and rhinoviruses in nearly half of stool and respiratory specimens. However, of 74 cases with a cerebral spinal fluid specimen, only 2 were positive for enteroviruses. All specimens tested negative for poliovirus.
But even when it is associated with a viral infection, it is not known how the infection triggered the AFM, or why it triggers AFM in some people and not others. AFM is rare—affecting ≤ 2 children per million in the US every year. Viral infections from enteroviruses are common, especially in children—and especially in the late summer/early autumn months. It is not known why a small number of people develop AFM while most others recover.
AFM can be difficult to diagnose because the symptoms are similar to those of neurologic diseases, such as Guillain-Barré syndrome. As of yet, no laboratory test is available; diagnosis is done through physical examination and magnetic resonance imaging (MRI) scans of the spinal cord.
There also are no proven ways to treat or prevent AFM. That is why timing is so key. The CDC says as soon as AFM is suspected, collect cerebral spinal fluid, serum, stool, and nasopharyngeal swabs. If an MRI shows a spinal lesion with some gray matter involvement, alert the health department and send specimens and medical records. Refer to specialists, monitor the patient for worsening symptoms, hospitalize if indicated, and begin treatment and rehabilitation.
In short: no specific etiology, no specific way to diagnose, and no specific treatment exist for AFM. Treatments, including immunoglobulin, corticosteroids, and antivirals have been tried, but no clear evidence exists that any have affected recovery. Other treatment is supportive, with physical and occupational therapy.
The length of recovery time varies. Some people make a full recovery, most have continued muscle weakness even after a year.
The CDC is researching possible risk factors, conducting advanced laboratory testing and research to determine how viral infections may lead to AFM, and tracking long-term patient outcomes.
Clinicians can contact neurologists who specialize in AFM through the AFM Physician Consult and Support Portal: https://myelitis.org/living-with-myelitis/resources/afm-physician-support-portal/.
Late summer is the season to be especially alert for possible cases of acute flaccid myelitis (AFM), the CDC says.
Since 2014, when the CDC began tracking AFM, 570 cases, mostly in children, have been reported. Outbreaks have followed a pattern: every 2 years, spiking between August and October. Nearly all states and DC have reported cases. The largest outbreak, 233 cases, was in 2018. Theoretically, 2019 would be an off year, but too little is known about AFM to say outbreaks are unlikely.
AFM starts with symptoms similar to those of a viral infection but can progress rapidly to limb weakness, then respiratory failure. Most patients are previously healthy children, average age 5 years old, who had respiratory symptoms or fever consistent with a viral infection less than a week before they experienced sudden weakness in their arms or legs. On average, the CDC receives reports of suspected AFM cases 18 days after the patient develops limb weakness.
The CDC believes viruses play a role, but which ones is still unclear. Symptoms have been found to develop after poliovirus, West Nile virus, and adenovirus infections. In an analysis of confirmed cases from 2018, CDC researchers detected enteroviruses and rhinoviruses in nearly half of stool and respiratory specimens. However, of 74 cases with a cerebral spinal fluid specimen, only 2 were positive for enteroviruses. All specimens tested negative for poliovirus.
But even when it is associated with a viral infection, it is not known how the infection triggered the AFM, or why it triggers AFM in some people and not others. AFM is rare—affecting ≤ 2 children per million in the US every year. Viral infections from enteroviruses are common, especially in children—and especially in the late summer/early autumn months. It is not known why a small number of people develop AFM while most others recover.
AFM can be difficult to diagnose because the symptoms are similar to those of neurologic diseases, such as Guillain-Barré syndrome. As of yet, no laboratory test is available; diagnosis is done through physical examination and magnetic resonance imaging (MRI) scans of the spinal cord.
There also are no proven ways to treat or prevent AFM. That is why timing is so key. The CDC says as soon as AFM is suspected, collect cerebral spinal fluid, serum, stool, and nasopharyngeal swabs. If an MRI shows a spinal lesion with some gray matter involvement, alert the health department and send specimens and medical records. Refer to specialists, monitor the patient for worsening symptoms, hospitalize if indicated, and begin treatment and rehabilitation.
In short: no specific etiology, no specific way to diagnose, and no specific treatment exist for AFM. Treatments, including immunoglobulin, corticosteroids, and antivirals have been tried, but no clear evidence exists that any have affected recovery. Other treatment is supportive, with physical and occupational therapy.
The length of recovery time varies. Some people make a full recovery, most have continued muscle weakness even after a year.
The CDC is researching possible risk factors, conducting advanced laboratory testing and research to determine how viral infections may lead to AFM, and tracking long-term patient outcomes.
Clinicians can contact neurologists who specialize in AFM through the AFM Physician Consult and Support Portal: https://myelitis.org/living-with-myelitis/resources/afm-physician-support-portal/.
Guidelines update donor selection criteria for HSCT
Newly updated guidelines can inform the selection of adult donors and cord blood units for allogeneic hematopoietic stem cell transplant.
The evidence-based guidelines suggest high-resolution human leukocyte antigen (HLA) matching and donor age are important when selecting adult donors, while HLA matching, cell dose, and banking practices should be considered when selecting cord blood units.
The guidelines were developed by the National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR) and were recently published in Blood.
Adult donors
The guidelines recommend high-resolution HLA typing for adult donors and patients. This means typing for HLA-A, -B, -C, and -DRB1, at minimum. Typing at other loci – DPB1, DQB1, DRB3/4/5, DQA1, and DPA1 – is “optional but often helpful.”
An 8/8 HLA-matched donor is considered optimal. If only 7/8-matched donors are available, select a donor with a single allele mismatched at the patient’s homozygous locus if possible, and select an HLA-C*03:03 mismatch over an HLA-C*03:04 mismatch where applicable.
For both 8/8- and 7/8-matched donors, try to avoid mismatches at DQB1 and DRB3/4/5, and select DPB1 mismatches based on the DPB1 T-cell epitope algorithm. Mismatches of allotypes targeted by donor-specific HLA antibodies (DSA), including DQA1 and DPA1, should be avoided.
The guidelines recommend pursuing multiple donors because not all potential donors will be available. Younger donors should be prioritized over older donors. Other factors – such as sex or cytomegalovirus serostatus – should not affect donor selection.
Cord blood
For cord blood donations, testing attached segment identity is mandatory, red blood cell–replete units are not recommended, and both unit cryovolume and year of cryopreservation should be taken into consideration. The guidelines note that “some expert centers” favor red blood cell–depleted units with a postcryopreservation volume of about 25 ml/bag, and units banked more recently “may be linked to optimal banking practices.”
The guidelines recommend a minimum of eight high-resolution HLA typing for cord blood units and patients. A 4/6 match (HLA-A, -B, -DRB1) is acceptable, as is a 4/8 match (HLA-A, -B, -C, and -DRB1) or greater. In the case of a double-unit transplant, there is no need to match the units to each other.
“DSA must be considered on a case-by-case basis,” according to the guidelines. The patient’s diagnosis, prior immunosuppressive therapy, planned conditioning regimen, and DSA number/titer/specificity/complement fixation should be taken into consideration. DSA-targeted units should be avoided in patients with nonmalignant conditions and used with caution in patients with hematologic malignancies.
For single–cord blood units, the total nucleated cell dose should be at least 2.5 x 107/kg, and the number of CD34+ cells should be at least 1.5 x 105/kg. For double-unit transplants, the total nucleated cell dose should be at least 1.5 x 107/kg for each unit, and the number of CD34+ cells should be at least 1.0 x 105/kg for each unit.
The guidelines note that additional research is needed to inform how to balance cell dose against HLA match. However, cell dose should often take priority over HLA match for adults and larger pediatric patients, and HLA match can take priority in children, smaller adults, or patients with common HLA typing who have multiple units with a high cell dose.
The guidelines’ authors reported relationships with MolMed, NexImmune, AbbVie, Bellicum, Incyte, Medigene, Merck, Nektar, Novartis, Servier, Miltenyi, and the U.S. government/military.
SOURCE: Dehn J et al. Blood. 2019 Jul 10. doi: 10.1182/blood.2019001212.
Newly updated guidelines can inform the selection of adult donors and cord blood units for allogeneic hematopoietic stem cell transplant.
The evidence-based guidelines suggest high-resolution human leukocyte antigen (HLA) matching and donor age are important when selecting adult donors, while HLA matching, cell dose, and banking practices should be considered when selecting cord blood units.
The guidelines were developed by the National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR) and were recently published in Blood.
Adult donors
The guidelines recommend high-resolution HLA typing for adult donors and patients. This means typing for HLA-A, -B, -C, and -DRB1, at minimum. Typing at other loci – DPB1, DQB1, DRB3/4/5, DQA1, and DPA1 – is “optional but often helpful.”
An 8/8 HLA-matched donor is considered optimal. If only 7/8-matched donors are available, select a donor with a single allele mismatched at the patient’s homozygous locus if possible, and select an HLA-C*03:03 mismatch over an HLA-C*03:04 mismatch where applicable.
For both 8/8- and 7/8-matched donors, try to avoid mismatches at DQB1 and DRB3/4/5, and select DPB1 mismatches based on the DPB1 T-cell epitope algorithm. Mismatches of allotypes targeted by donor-specific HLA antibodies (DSA), including DQA1 and DPA1, should be avoided.
The guidelines recommend pursuing multiple donors because not all potential donors will be available. Younger donors should be prioritized over older donors. Other factors – such as sex or cytomegalovirus serostatus – should not affect donor selection.
Cord blood
For cord blood donations, testing attached segment identity is mandatory, red blood cell–replete units are not recommended, and both unit cryovolume and year of cryopreservation should be taken into consideration. The guidelines note that “some expert centers” favor red blood cell–depleted units with a postcryopreservation volume of about 25 ml/bag, and units banked more recently “may be linked to optimal banking practices.”
The guidelines recommend a minimum of eight high-resolution HLA typing for cord blood units and patients. A 4/6 match (HLA-A, -B, -DRB1) is acceptable, as is a 4/8 match (HLA-A, -B, -C, and -DRB1) or greater. In the case of a double-unit transplant, there is no need to match the units to each other.
“DSA must be considered on a case-by-case basis,” according to the guidelines. The patient’s diagnosis, prior immunosuppressive therapy, planned conditioning regimen, and DSA number/titer/specificity/complement fixation should be taken into consideration. DSA-targeted units should be avoided in patients with nonmalignant conditions and used with caution in patients with hematologic malignancies.
For single–cord blood units, the total nucleated cell dose should be at least 2.5 x 107/kg, and the number of CD34+ cells should be at least 1.5 x 105/kg. For double-unit transplants, the total nucleated cell dose should be at least 1.5 x 107/kg for each unit, and the number of CD34+ cells should be at least 1.0 x 105/kg for each unit.
The guidelines note that additional research is needed to inform how to balance cell dose against HLA match. However, cell dose should often take priority over HLA match for adults and larger pediatric patients, and HLA match can take priority in children, smaller adults, or patients with common HLA typing who have multiple units with a high cell dose.
The guidelines’ authors reported relationships with MolMed, NexImmune, AbbVie, Bellicum, Incyte, Medigene, Merck, Nektar, Novartis, Servier, Miltenyi, and the U.S. government/military.
SOURCE: Dehn J et al. Blood. 2019 Jul 10. doi: 10.1182/blood.2019001212.
Newly updated guidelines can inform the selection of adult donors and cord blood units for allogeneic hematopoietic stem cell transplant.
The evidence-based guidelines suggest high-resolution human leukocyte antigen (HLA) matching and donor age are important when selecting adult donors, while HLA matching, cell dose, and banking practices should be considered when selecting cord blood units.
The guidelines were developed by the National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR) and were recently published in Blood.
Adult donors
The guidelines recommend high-resolution HLA typing for adult donors and patients. This means typing for HLA-A, -B, -C, and -DRB1, at minimum. Typing at other loci – DPB1, DQB1, DRB3/4/5, DQA1, and DPA1 – is “optional but often helpful.”
An 8/8 HLA-matched donor is considered optimal. If only 7/8-matched donors are available, select a donor with a single allele mismatched at the patient’s homozygous locus if possible, and select an HLA-C*03:03 mismatch over an HLA-C*03:04 mismatch where applicable.
For both 8/8- and 7/8-matched donors, try to avoid mismatches at DQB1 and DRB3/4/5, and select DPB1 mismatches based on the DPB1 T-cell epitope algorithm. Mismatches of allotypes targeted by donor-specific HLA antibodies (DSA), including DQA1 and DPA1, should be avoided.
The guidelines recommend pursuing multiple donors because not all potential donors will be available. Younger donors should be prioritized over older donors. Other factors – such as sex or cytomegalovirus serostatus – should not affect donor selection.
Cord blood
For cord blood donations, testing attached segment identity is mandatory, red blood cell–replete units are not recommended, and both unit cryovolume and year of cryopreservation should be taken into consideration. The guidelines note that “some expert centers” favor red blood cell–depleted units with a postcryopreservation volume of about 25 ml/bag, and units banked more recently “may be linked to optimal banking practices.”
The guidelines recommend a minimum of eight high-resolution HLA typing for cord blood units and patients. A 4/6 match (HLA-A, -B, -DRB1) is acceptable, as is a 4/8 match (HLA-A, -B, -C, and -DRB1) or greater. In the case of a double-unit transplant, there is no need to match the units to each other.
“DSA must be considered on a case-by-case basis,” according to the guidelines. The patient’s diagnosis, prior immunosuppressive therapy, planned conditioning regimen, and DSA number/titer/specificity/complement fixation should be taken into consideration. DSA-targeted units should be avoided in patients with nonmalignant conditions and used with caution in patients with hematologic malignancies.
For single–cord blood units, the total nucleated cell dose should be at least 2.5 x 107/kg, and the number of CD34+ cells should be at least 1.5 x 105/kg. For double-unit transplants, the total nucleated cell dose should be at least 1.5 x 107/kg for each unit, and the number of CD34+ cells should be at least 1.0 x 105/kg for each unit.
The guidelines note that additional research is needed to inform how to balance cell dose against HLA match. However, cell dose should often take priority over HLA match for adults and larger pediatric patients, and HLA match can take priority in children, smaller adults, or patients with common HLA typing who have multiple units with a high cell dose.
The guidelines’ authors reported relationships with MolMed, NexImmune, AbbVie, Bellicum, Incyte, Medigene, Merck, Nektar, Novartis, Servier, Miltenyi, and the U.S. government/military.
SOURCE: Dehn J et al. Blood. 2019 Jul 10. doi: 10.1182/blood.2019001212.
FROM BLOOD
Large genetic cohort supports NfL as Alzheimer’s biomarker
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.
At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.
While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.
Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).
Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.
“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”
A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).
In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”
Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”
Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.
“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.
Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”
Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”
Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.
REPORTING FROM AAIC 2019
Exercise counters astronauts’ dizziness after space flight
Months of spaceflight can leave astronauts feeling dizzy when they get back to terra firma. A new study published online in Circulation shows that up to 2 hours of daily resistance and endurance training during the mission, combined with IV fluid replacement upon return to Earth, completely eliminated dizziness and fainting during normal activity. The exercise regimen counters cardiovascular, bone, and muscular deconditioning.
The dizziness is related to low blood pressure after standing up from a sitting or lying down position. It results when blood rushes to the feet and away from the brain because of the movement. The phenomenon, known as orthostatic hypotension, has plagued the space program even before the Apollo 11 mission, which celebrates its 50th anniversary this week.
The finding is good news for astronauts, but the findings extend to full-time Earthlings as well. The same fitness program is helping patients with postural orthostatic tachycardia syndrome (POTS), which most often affects women aged 13-50 years, said senior author Benjamin Levine, MD. About 450,000 people suffer from the condition in the United States.
The program held up well against a difficult challenge. “What surprised me the most was how well the astronauts did after spending 6 months in space. I thought there would be frequent episodes of fainting when they returned to Earth, but they didn’t have any. It’s compelling evidence of the effectiveness of the countermeasures – the exercise regimen and fluid replenishment,” said Dr. Levine, who is professor of Exercise Sciences at UT Southwestern Medical Center, said in a press release.
The researchers studied 12 astronauts (8 men, 4 women) who were aboard the International Space Station for roughly 6 months. To monitor for orthostatic hypotension, the researchers used ambulatory beat-to-beat blood pressure monitoring during activities of daily living. The device was used for 24 hour periods before, during (day 15, 30, and 75, as well as 15 days before return to Earth), and immediately following space flight.
The research showed that 24-hour systolic blood pressure decreased, compared with preflight levels, during flight time (106 vs 120 mm Hg; P less than .01), but the values returned to normal after return to Earth (122 mm Hg). There was no change in diastolic BP during or after flight. Systolic and diastolic BP variability did not change before, during, and after flight.
The study was funded by NASA. Dr. Levine has no disclosures.
SOURCE: Qi Fu et al. Circulation. 2019 July 19. doi: 10.1161/CIRCULATIONAHA.119.041050.
Months of spaceflight can leave astronauts feeling dizzy when they get back to terra firma. A new study published online in Circulation shows that up to 2 hours of daily resistance and endurance training during the mission, combined with IV fluid replacement upon return to Earth, completely eliminated dizziness and fainting during normal activity. The exercise regimen counters cardiovascular, bone, and muscular deconditioning.
The dizziness is related to low blood pressure after standing up from a sitting or lying down position. It results when blood rushes to the feet and away from the brain because of the movement. The phenomenon, known as orthostatic hypotension, has plagued the space program even before the Apollo 11 mission, which celebrates its 50th anniversary this week.
The finding is good news for astronauts, but the findings extend to full-time Earthlings as well. The same fitness program is helping patients with postural orthostatic tachycardia syndrome (POTS), which most often affects women aged 13-50 years, said senior author Benjamin Levine, MD. About 450,000 people suffer from the condition in the United States.
The program held up well against a difficult challenge. “What surprised me the most was how well the astronauts did after spending 6 months in space. I thought there would be frequent episodes of fainting when they returned to Earth, but they didn’t have any. It’s compelling evidence of the effectiveness of the countermeasures – the exercise regimen and fluid replenishment,” said Dr. Levine, who is professor of Exercise Sciences at UT Southwestern Medical Center, said in a press release.
The researchers studied 12 astronauts (8 men, 4 women) who were aboard the International Space Station for roughly 6 months. To monitor for orthostatic hypotension, the researchers used ambulatory beat-to-beat blood pressure monitoring during activities of daily living. The device was used for 24 hour periods before, during (day 15, 30, and 75, as well as 15 days before return to Earth), and immediately following space flight.
The research showed that 24-hour systolic blood pressure decreased, compared with preflight levels, during flight time (106 vs 120 mm Hg; P less than .01), but the values returned to normal after return to Earth (122 mm Hg). There was no change in diastolic BP during or after flight. Systolic and diastolic BP variability did not change before, during, and after flight.
The study was funded by NASA. Dr. Levine has no disclosures.
SOURCE: Qi Fu et al. Circulation. 2019 July 19. doi: 10.1161/CIRCULATIONAHA.119.041050.
Months of spaceflight can leave astronauts feeling dizzy when they get back to terra firma. A new study published online in Circulation shows that up to 2 hours of daily resistance and endurance training during the mission, combined with IV fluid replacement upon return to Earth, completely eliminated dizziness and fainting during normal activity. The exercise regimen counters cardiovascular, bone, and muscular deconditioning.
The dizziness is related to low blood pressure after standing up from a sitting or lying down position. It results when blood rushes to the feet and away from the brain because of the movement. The phenomenon, known as orthostatic hypotension, has plagued the space program even before the Apollo 11 mission, which celebrates its 50th anniversary this week.
The finding is good news for astronauts, but the findings extend to full-time Earthlings as well. The same fitness program is helping patients with postural orthostatic tachycardia syndrome (POTS), which most often affects women aged 13-50 years, said senior author Benjamin Levine, MD. About 450,000 people suffer from the condition in the United States.
The program held up well against a difficult challenge. “What surprised me the most was how well the astronauts did after spending 6 months in space. I thought there would be frequent episodes of fainting when they returned to Earth, but they didn’t have any. It’s compelling evidence of the effectiveness of the countermeasures – the exercise regimen and fluid replenishment,” said Dr. Levine, who is professor of Exercise Sciences at UT Southwestern Medical Center, said in a press release.
The researchers studied 12 astronauts (8 men, 4 women) who were aboard the International Space Station for roughly 6 months. To monitor for orthostatic hypotension, the researchers used ambulatory beat-to-beat blood pressure monitoring during activities of daily living. The device was used for 24 hour periods before, during (day 15, 30, and 75, as well as 15 days before return to Earth), and immediately following space flight.
The research showed that 24-hour systolic blood pressure decreased, compared with preflight levels, during flight time (106 vs 120 mm Hg; P less than .01), but the values returned to normal after return to Earth (122 mm Hg). There was no change in diastolic BP during or after flight. Systolic and diastolic BP variability did not change before, during, and after flight.
The study was funded by NASA. Dr. Levine has no disclosures.
SOURCE: Qi Fu et al. Circulation. 2019 July 19. doi: 10.1161/CIRCULATIONAHA.119.041050.
REPORTING FROM CIRCULATION
IL-6, CRP are prognostic for checkpoint inhibition in melanoma
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
CHICAGO – according to post hoc analyses of data from three randomized CheckMate studies.
In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.
After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.
“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.
This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.
Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).
“So this is not a predictive marker, this is a baseline prognostic marker,” he said.
In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).
A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.
“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.
In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.
For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).
In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.
In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).
To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.
Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.
“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.
The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”
To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.
During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”
“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”
Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.
“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”
Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses
SOURCE: Weber J et al. ASCO 2019, Abstract 100.
REPORTING FROM ASCO 2019