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Overreliance on DAS scores undermines rheumatoid arthritis management
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
REPORTING FROM EULAR 2019 CONGRESS
Drug efficacy in phase 2 RA trials often missing in phase 3
MADRID – The efficacy results from new rheumatoid arthritis drugs tested in many phase 2 trials run over the past couple of decades have routinely overestimated the efficacy of many of the drugs tested when compared with how the same agents performed in subsequent phase 3 testing, according to an analysis of published results from 44 pairs of phase 2 and 3 trials.
Based on the percentage of rheumatoid arthritis (RA) patients who showed an American College of Rheumatology 20% improvement (ACR20) in their joint symptoms, the 44 phase 2 trials overestimated efficacy by an average of 39% when compared with the ACR20 responses seen in paired phase 3 trials, Andreas Kerschbaumer, MD, said at the European Congress of Rheumatology. The ACR50 results overstated efficacy by an average of 34% when compared with phase 3 results for the same drugs, and the ACR70 endpoint showed drug efficacy that averaged 39% better during phase 2 studies than it did in the phase 3 trials. All three between-group differences were statistically significant, said Dr. Kerschbaumer, a rheumatologist at the Medical University of Vienna.
“Active treatment arms of phase 2 studies systematically overestimated efficacy when compared with subsequent phase 3 studies,” he said.
“Many researchers had already seen this, and realized that phase 2 trials often overestimated [efficacy], but no one has ever shown this systematically,” Dr. Kerschbaumer said in an interview. The same problem also appears to affect trials of oncology drugs, he noted, but a unique feature of RA studies allowed him and his colleagues to examine the ubiquity and persistence of this phase 2 bias in rheumatology trials over time: ongoing reliance during more than 2 decades of experience on the ACR20 response as the primary endpoint of RA drug trials. Even with this advantage, which allowed inclusion of 44 pairs of studies, “it was very surprising to find a statistically significant effect in the meta-analysis,” he said.
He and his associates also ran a further analysis that looked for measured parameters that showed significant correlation with mismatch of the phase 2 and 3 results, and this identified two apparently causal factors: having a low number of swollen and tender joints as an inclusion criterion for patients and using a 28-joint count rather than a 66-joint count for assessing disease activity during the study. The analysis lacked enough information to provide clear evidence on why these two aspects of patient assessment could lead to misleading phase 2 results, but Dr. Kerschbaumer believed the findings were clear enough to influence future trial design.
Going forward, trialists “should be very careful of how you include patients [in studies]. This is what our study shows. And they should not use 28 joints but 66. The higher the number of swollen and tender joints detected for study inclusion, the less the possibility to overestimate [efficacy]. It’s easier to achieve ACR20 when you look at fewer joints.”
Until now, companies that sponsor drug trials had an incentive to use a lower minimum number of swollen and tender joints for enrolled patients because it made enrollment easier, he noted. The downside, in addition to overstating efficacy at the phase 2 stage, is subjecting patients to treatments in phase 3 trials with a reduced likelihood for success.
Dr. Kerschbaumer offered two examples of drugs that showed promising RA efficacy based on ACR20 responses in phase 2 trial results that were followed by neutral phase 3 trial outcomes. One episode involved tabalumab (Ann Rheum Dis. 2015 Aug;74[8]:1567-70), and a second was a trial of fostamatinib (Arthritis Rheumatol. 2014 Dec;66[12]:3255-64).
The systematic review he led identified 44 study pairs run since the late 1990s that met all the study criteria, which covered 19 different drugs tested in more than 17,000 RA patients.
What the results showed was “just an association, so we must be careful not to overstate the results, but we saw something that may explain what people have seen [anecdotally] over the past 20 years,” he said. “Some people get very excited by phase 2 results, but we need to be careful about interpreting these outcomes.” Validation of the finding would require analysis of patient-level data, something that would be hard to obtain for a large number of phase 2 and 3 trials, Dr. Kerschbaumer noted.
Dr. Kerschbaumer has been a speaker on behalf of Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, and Pfizer.
SOURCE: Kerschbaumer A et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):191-2. Abstract OP0229, doi: 10.1136/annrheumdis-2019-eular.5161.
MADRID – The efficacy results from new rheumatoid arthritis drugs tested in many phase 2 trials run over the past couple of decades have routinely overestimated the efficacy of many of the drugs tested when compared with how the same agents performed in subsequent phase 3 testing, according to an analysis of published results from 44 pairs of phase 2 and 3 trials.
Based on the percentage of rheumatoid arthritis (RA) patients who showed an American College of Rheumatology 20% improvement (ACR20) in their joint symptoms, the 44 phase 2 trials overestimated efficacy by an average of 39% when compared with the ACR20 responses seen in paired phase 3 trials, Andreas Kerschbaumer, MD, said at the European Congress of Rheumatology. The ACR50 results overstated efficacy by an average of 34% when compared with phase 3 results for the same drugs, and the ACR70 endpoint showed drug efficacy that averaged 39% better during phase 2 studies than it did in the phase 3 trials. All three between-group differences were statistically significant, said Dr. Kerschbaumer, a rheumatologist at the Medical University of Vienna.
“Active treatment arms of phase 2 studies systematically overestimated efficacy when compared with subsequent phase 3 studies,” he said.
“Many researchers had already seen this, and realized that phase 2 trials often overestimated [efficacy], but no one has ever shown this systematically,” Dr. Kerschbaumer said in an interview. The same problem also appears to affect trials of oncology drugs, he noted, but a unique feature of RA studies allowed him and his colleagues to examine the ubiquity and persistence of this phase 2 bias in rheumatology trials over time: ongoing reliance during more than 2 decades of experience on the ACR20 response as the primary endpoint of RA drug trials. Even with this advantage, which allowed inclusion of 44 pairs of studies, “it was very surprising to find a statistically significant effect in the meta-analysis,” he said.
He and his associates also ran a further analysis that looked for measured parameters that showed significant correlation with mismatch of the phase 2 and 3 results, and this identified two apparently causal factors: having a low number of swollen and tender joints as an inclusion criterion for patients and using a 28-joint count rather than a 66-joint count for assessing disease activity during the study. The analysis lacked enough information to provide clear evidence on why these two aspects of patient assessment could lead to misleading phase 2 results, but Dr. Kerschbaumer believed the findings were clear enough to influence future trial design.
Going forward, trialists “should be very careful of how you include patients [in studies]. This is what our study shows. And they should not use 28 joints but 66. The higher the number of swollen and tender joints detected for study inclusion, the less the possibility to overestimate [efficacy]. It’s easier to achieve ACR20 when you look at fewer joints.”
Until now, companies that sponsor drug trials had an incentive to use a lower minimum number of swollen and tender joints for enrolled patients because it made enrollment easier, he noted. The downside, in addition to overstating efficacy at the phase 2 stage, is subjecting patients to treatments in phase 3 trials with a reduced likelihood for success.
Dr. Kerschbaumer offered two examples of drugs that showed promising RA efficacy based on ACR20 responses in phase 2 trial results that were followed by neutral phase 3 trial outcomes. One episode involved tabalumab (Ann Rheum Dis. 2015 Aug;74[8]:1567-70), and a second was a trial of fostamatinib (Arthritis Rheumatol. 2014 Dec;66[12]:3255-64).
The systematic review he led identified 44 study pairs run since the late 1990s that met all the study criteria, which covered 19 different drugs tested in more than 17,000 RA patients.
What the results showed was “just an association, so we must be careful not to overstate the results, but we saw something that may explain what people have seen [anecdotally] over the past 20 years,” he said. “Some people get very excited by phase 2 results, but we need to be careful about interpreting these outcomes.” Validation of the finding would require analysis of patient-level data, something that would be hard to obtain for a large number of phase 2 and 3 trials, Dr. Kerschbaumer noted.
Dr. Kerschbaumer has been a speaker on behalf of Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, and Pfizer.
SOURCE: Kerschbaumer A et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):191-2. Abstract OP0229, doi: 10.1136/annrheumdis-2019-eular.5161.
MADRID – The efficacy results from new rheumatoid arthritis drugs tested in many phase 2 trials run over the past couple of decades have routinely overestimated the efficacy of many of the drugs tested when compared with how the same agents performed in subsequent phase 3 testing, according to an analysis of published results from 44 pairs of phase 2 and 3 trials.
Based on the percentage of rheumatoid arthritis (RA) patients who showed an American College of Rheumatology 20% improvement (ACR20) in their joint symptoms, the 44 phase 2 trials overestimated efficacy by an average of 39% when compared with the ACR20 responses seen in paired phase 3 trials, Andreas Kerschbaumer, MD, said at the European Congress of Rheumatology. The ACR50 results overstated efficacy by an average of 34% when compared with phase 3 results for the same drugs, and the ACR70 endpoint showed drug efficacy that averaged 39% better during phase 2 studies than it did in the phase 3 trials. All three between-group differences were statistically significant, said Dr. Kerschbaumer, a rheumatologist at the Medical University of Vienna.
“Active treatment arms of phase 2 studies systematically overestimated efficacy when compared with subsequent phase 3 studies,” he said.
“Many researchers had already seen this, and realized that phase 2 trials often overestimated [efficacy], but no one has ever shown this systematically,” Dr. Kerschbaumer said in an interview. The same problem also appears to affect trials of oncology drugs, he noted, but a unique feature of RA studies allowed him and his colleagues to examine the ubiquity and persistence of this phase 2 bias in rheumatology trials over time: ongoing reliance during more than 2 decades of experience on the ACR20 response as the primary endpoint of RA drug trials. Even with this advantage, which allowed inclusion of 44 pairs of studies, “it was very surprising to find a statistically significant effect in the meta-analysis,” he said.
He and his associates also ran a further analysis that looked for measured parameters that showed significant correlation with mismatch of the phase 2 and 3 results, and this identified two apparently causal factors: having a low number of swollen and tender joints as an inclusion criterion for patients and using a 28-joint count rather than a 66-joint count for assessing disease activity during the study. The analysis lacked enough information to provide clear evidence on why these two aspects of patient assessment could lead to misleading phase 2 results, but Dr. Kerschbaumer believed the findings were clear enough to influence future trial design.
Going forward, trialists “should be very careful of how you include patients [in studies]. This is what our study shows. And they should not use 28 joints but 66. The higher the number of swollen and tender joints detected for study inclusion, the less the possibility to overestimate [efficacy]. It’s easier to achieve ACR20 when you look at fewer joints.”
Until now, companies that sponsor drug trials had an incentive to use a lower minimum number of swollen and tender joints for enrolled patients because it made enrollment easier, he noted. The downside, in addition to overstating efficacy at the phase 2 stage, is subjecting patients to treatments in phase 3 trials with a reduced likelihood for success.
Dr. Kerschbaumer offered two examples of drugs that showed promising RA efficacy based on ACR20 responses in phase 2 trial results that were followed by neutral phase 3 trial outcomes. One episode involved tabalumab (Ann Rheum Dis. 2015 Aug;74[8]:1567-70), and a second was a trial of fostamatinib (Arthritis Rheumatol. 2014 Dec;66[12]:3255-64).
The systematic review he led identified 44 study pairs run since the late 1990s that met all the study criteria, which covered 19 different drugs tested in more than 17,000 RA patients.
What the results showed was “just an association, so we must be careful not to overstate the results, but we saw something that may explain what people have seen [anecdotally] over the past 20 years,” he said. “Some people get very excited by phase 2 results, but we need to be careful about interpreting these outcomes.” Validation of the finding would require analysis of patient-level data, something that would be hard to obtain for a large number of phase 2 and 3 trials, Dr. Kerschbaumer noted.
Dr. Kerschbaumer has been a speaker on behalf of Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, and Pfizer.
SOURCE: Kerschbaumer A et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):191-2. Abstract OP0229, doi: 10.1136/annrheumdis-2019-eular.5161.
REPORTING FROM EULAR 2019 CONGRESS
Flu vaccine succeeds in TNF inhibitor users
MADRID – Influenza vaccination is similarly effective for individuals taking a tumor necrosis factor (TNF) inhibitor and healthy controls, but the number needed to vaccinate to prevent one case of influenza for patients taking a TNF inhibitor is much lower, according to data from a study presented at the European Congress of Rheumatology.
The number needed to vaccinate (NNV) to prevent one case of influenza among healthy control patients was 71, compared with an NNV of 10 for patients taking the TNF inhibitor adalimumab (Humira), reported Giovanni Adami, MD, and colleagues at the University of Verona (Italy).
While TNF inhibitors “are known to increase the risk of infection by suppressing the activity of the immune system,” it has not been clear whether the response to vaccination is impaired in patients treated with a TNF inhibitor, Dr. Adami said.
Dr. Adami and colleagues reviewed data from 15,132 adult patients exposed to adalimumab in global rheumatoid arthritis clinical trials and 71,221 healthy controls from clinical trials of influenza vaccines. Overall, the rate of influenza infection was similarly reduced with vaccination in both groups. The rate in healthy individuals went from 2.3% for those unvaccinated to 0.9% for those vaccinated; for TNF inhibitor–treated patients, the rate was 14.4% for those unvaccinated versus 4.5% for those vaccinated.
“It is not surprising that the number needed to vaccinate is dramatically lower in patients treated with immunosuppressors, compared to healthy individuals,” Dr. Adami noted. “As a matter of fact, patients treated with such drugs are at higher risk of infections, namely they have a greater absolute risk of influenza. Nevertheless, [it] is quite surprising that the relative risk reduction is similar between TNF inhibitor–treated patients and healthy controls, meaning that the vaccination is efficacious in both the cohorts.”
The researchers also calculated the cost to prevent one case of influenza, using a cost of approximately 16.5 euro per vaccine. (Dr. Adami also cited an average U.S. cost of about $40/vaccine). Using this method, they estimated a cost for vaccination of 1,174 euro (roughly $1,340) to prevent one influenza infection in the general population, and a cost of about 165 euro (roughly $188) to vaccinate enough people treated with a TNF inhibitor to prevent one infection.
Dr. Adami advised clinicians to remember the low NNV for TNF inhibitor–treated patients with regard to influenza vaccination. “A direct disclosure of the NNV for these patients might help adherence to vaccinations,” he said.
Next steps for research should include extending the real-world effectiveness analysis to other medications and other diseases, such as zoster vaccination in patients treated with Janus kinase inhibitors, Dr. Adami said.
Dr. Adami had no financial conflicts to disclose. Several coauthors disclosed relationships with companies including Abiogen Pharma, Grünenthal, Amgen, Janssen-Cilag, Mundipharma, and Pfizer.
Mitchel L. Zoler contributed to this report.
SOURCE: Adami G et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):192-3. Abstract OP0230, doi: 10.1136/annrheumdis-2019-eular.3088
MADRID – Influenza vaccination is similarly effective for individuals taking a tumor necrosis factor (TNF) inhibitor and healthy controls, but the number needed to vaccinate to prevent one case of influenza for patients taking a TNF inhibitor is much lower, according to data from a study presented at the European Congress of Rheumatology.
The number needed to vaccinate (NNV) to prevent one case of influenza among healthy control patients was 71, compared with an NNV of 10 for patients taking the TNF inhibitor adalimumab (Humira), reported Giovanni Adami, MD, and colleagues at the University of Verona (Italy).
While TNF inhibitors “are known to increase the risk of infection by suppressing the activity of the immune system,” it has not been clear whether the response to vaccination is impaired in patients treated with a TNF inhibitor, Dr. Adami said.
Dr. Adami and colleagues reviewed data from 15,132 adult patients exposed to adalimumab in global rheumatoid arthritis clinical trials and 71,221 healthy controls from clinical trials of influenza vaccines. Overall, the rate of influenza infection was similarly reduced with vaccination in both groups. The rate in healthy individuals went from 2.3% for those unvaccinated to 0.9% for those vaccinated; for TNF inhibitor–treated patients, the rate was 14.4% for those unvaccinated versus 4.5% for those vaccinated.
“It is not surprising that the number needed to vaccinate is dramatically lower in patients treated with immunosuppressors, compared to healthy individuals,” Dr. Adami noted. “As a matter of fact, patients treated with such drugs are at higher risk of infections, namely they have a greater absolute risk of influenza. Nevertheless, [it] is quite surprising that the relative risk reduction is similar between TNF inhibitor–treated patients and healthy controls, meaning that the vaccination is efficacious in both the cohorts.”
The researchers also calculated the cost to prevent one case of influenza, using a cost of approximately 16.5 euro per vaccine. (Dr. Adami also cited an average U.S. cost of about $40/vaccine). Using this method, they estimated a cost for vaccination of 1,174 euro (roughly $1,340) to prevent one influenza infection in the general population, and a cost of about 165 euro (roughly $188) to vaccinate enough people treated with a TNF inhibitor to prevent one infection.
Dr. Adami advised clinicians to remember the low NNV for TNF inhibitor–treated patients with regard to influenza vaccination. “A direct disclosure of the NNV for these patients might help adherence to vaccinations,” he said.
Next steps for research should include extending the real-world effectiveness analysis to other medications and other diseases, such as zoster vaccination in patients treated with Janus kinase inhibitors, Dr. Adami said.
Dr. Adami had no financial conflicts to disclose. Several coauthors disclosed relationships with companies including Abiogen Pharma, Grünenthal, Amgen, Janssen-Cilag, Mundipharma, and Pfizer.
Mitchel L. Zoler contributed to this report.
SOURCE: Adami G et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):192-3. Abstract OP0230, doi: 10.1136/annrheumdis-2019-eular.3088
MADRID – Influenza vaccination is similarly effective for individuals taking a tumor necrosis factor (TNF) inhibitor and healthy controls, but the number needed to vaccinate to prevent one case of influenza for patients taking a TNF inhibitor is much lower, according to data from a study presented at the European Congress of Rheumatology.
The number needed to vaccinate (NNV) to prevent one case of influenza among healthy control patients was 71, compared with an NNV of 10 for patients taking the TNF inhibitor adalimumab (Humira), reported Giovanni Adami, MD, and colleagues at the University of Verona (Italy).
While TNF inhibitors “are known to increase the risk of infection by suppressing the activity of the immune system,” it has not been clear whether the response to vaccination is impaired in patients treated with a TNF inhibitor, Dr. Adami said.
Dr. Adami and colleagues reviewed data from 15,132 adult patients exposed to adalimumab in global rheumatoid arthritis clinical trials and 71,221 healthy controls from clinical trials of influenza vaccines. Overall, the rate of influenza infection was similarly reduced with vaccination in both groups. The rate in healthy individuals went from 2.3% for those unvaccinated to 0.9% for those vaccinated; for TNF inhibitor–treated patients, the rate was 14.4% for those unvaccinated versus 4.5% for those vaccinated.
“It is not surprising that the number needed to vaccinate is dramatically lower in patients treated with immunosuppressors, compared to healthy individuals,” Dr. Adami noted. “As a matter of fact, patients treated with such drugs are at higher risk of infections, namely they have a greater absolute risk of influenza. Nevertheless, [it] is quite surprising that the relative risk reduction is similar between TNF inhibitor–treated patients and healthy controls, meaning that the vaccination is efficacious in both the cohorts.”
The researchers also calculated the cost to prevent one case of influenza, using a cost of approximately 16.5 euro per vaccine. (Dr. Adami also cited an average U.S. cost of about $40/vaccine). Using this method, they estimated a cost for vaccination of 1,174 euro (roughly $1,340) to prevent one influenza infection in the general population, and a cost of about 165 euro (roughly $188) to vaccinate enough people treated with a TNF inhibitor to prevent one infection.
Dr. Adami advised clinicians to remember the low NNV for TNF inhibitor–treated patients with regard to influenza vaccination. “A direct disclosure of the NNV for these patients might help adherence to vaccinations,” he said.
Next steps for research should include extending the real-world effectiveness analysis to other medications and other diseases, such as zoster vaccination in patients treated with Janus kinase inhibitors, Dr. Adami said.
Dr. Adami had no financial conflicts to disclose. Several coauthors disclosed relationships with companies including Abiogen Pharma, Grünenthal, Amgen, Janssen-Cilag, Mundipharma, and Pfizer.
Mitchel L. Zoler contributed to this report.
SOURCE: Adami G et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):192-3. Abstract OP0230, doi: 10.1136/annrheumdis-2019-eular.3088
REPORTING FROM EULAR 2019 CONGRESS
Refractory RA responds to vagus nerve stimulation
MADRID –
A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.
The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.
“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.
“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.
He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”
Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.
“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.
Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.
For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.
Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.
All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.
“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”
While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.
Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”
The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.
SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716
MADRID –
A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.
The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.
“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.
“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.
He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”
Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.
“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.
Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.
For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.
Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.
All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.
“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”
While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.
Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”
The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.
SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716
MADRID –
A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.
The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.
“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.
“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.
He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”
Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.
“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.
Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.
For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.
Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.
All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.
“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”
While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.
Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”
The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.
SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716
REPORTING FROM EULAR 2019 CONGRESS
Imaging remission decried as ticket to RA overtreatment
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
MADRID – Defining remission in patients with rheumatoid arthritis depends on their clinical status, not on the presence or absence of inflammatory signals on ultrasound or MRI, many rheumatologists now agree.
The strong consensus that’s formed against using imaging as a criterion for RA remission was apparent at the European Congress of Rheumatology during presentation of a pending update to the EULAR recommendations for managing RA, as well as in at least two separate, invited lectures.
“Imaging is out,” proclaimed Josef S. Smolen, MD, as he spoke at the congress about the pending RA management revisions. This condemnation of imaging by ultrasound or MRI as an unsafe and misleading target for RA treatment by Dr. Smolen, professor of medicine at the Medical University of Vienna, was perhaps the most forceful statement he made while presenting the draft revision of EULAR’s RA recommendations.
The case for using ultrasound or MR to find inflammatory signatures in joints that can function as treatment targets collapsed earlier in 2019 with publication of results from IMAGINE-RA (An MRI-guided Treatment Strategy to Prevent Disease Progression in Patients With Rheumatoid Arthritis), a multicenter Danish study that randomized 200 RA patients in remission to either a conventional, disease activity–guided treatment target (in this case the DAS28-CRP [Disease Activity Score in 28 joints plus C-reactive protein]), or a treatment target that included the conventional clinical target plus treating to eliminate any bone marrow edema visualized by MRI. After 24 months of treatment, the prevalence of clinical remission and MRI remission was about the same in both arms, with no statistically significant differences. But serious adverse events in 6 patients managed by their clinical assessment compared favorably against 17 among those managed to an imaging remission endpoint, a difference that strongly hinted at dangerous overtreatment of the imaging-guided patients (JAMA. 2019 Feb 5;321[5]:461-72).
The failure of MRI assessment of inflammation to improve RA treatment in IMAGINE-RA came against the backdrop of two 2016 reports that documented the same limitation when using ultrasound to detect joint inflammation and guide treatment in RA patients. The TaSER (Targeting Synovitis in Early Rheumatoid Arthritis) study randomized 111 patients with newly diagnosed RA or undifferentiated arthritis to conventional disease activity assessment, DAS28–erythrocyte sedimentation rate, or to that plus assessment by musculoskeletal ultrasound, and found no difference in clinical or imaging outcomes (Ann Rheum Dis. 2016 Jun;75[6]:1043-50). The second report, ARCTIC (Aiming for Remission in Rheumatoid Arthritis), randomized 238 RA patients to either a tight RA control strategy based on DAS alone or based on DAS plus serial examination of joints with ultrasound. The results showed that, after 16-24 months on treatment, the two strategies produced no significant difference in the rates of sustained RA remission with no radiographic damage or swollen joints detected (BMJ. 2016 Aug 16;354:i4205).
The results from these three studies have shown that “not all inflammation seen by ultrasound or MR is pathological,” and that “no imaging technique or biomarker has shown superiority to clinical assessment as a treat-to-target” goal, Sofia Ramiro, MD, said in a talk at the congress during which she reviewed this evidence.
“Treat-to-target that takes imaging into account is high risk because it exposes patients to overtreatment, which has costs in the broad sense, safety included,” said Dr. Ramiro, a rheumatologist at Leiden (the Netherlands) University Medical Center. “I think that systematically evaluating a patient’s joint with imaging won’t have additional value, and is the wrong approach.”
A similar assessment came from Stefan Siebert, MD, during a separate lecture during the congress. He highlighted that use of ultrasound or MRI to guide treatment in these three studies consistently led to substantially higher rates of treatment escalation, treatment with biologics, and in two of the three studies a notable increase in serious adverse events. Treatment with a biologic drug was roughly twice as frequent in the imaging-guided arms of TaSER and ARCTIC, compared with the control arms in those studies, and in IMAGINE-RA, the use of a biologic drug occurred more than 20 times more often in the imaging arms, he noted. And in both TaSER and IMAGINE-RA the rate of serious adverse events was more than doubled in the imaging arms, compared with the controls.
“Just identifying inflammation [in a joint] is not enough to make a diagnosis. Inflammation is normal process, and finding it does not identify a pathological state,” noted Dr. Siebert, a rheumatologist at the University of Glasgow. “Imaging leads to overdiagnosis and overtreatment when physicians use imaging inappropriately,” he concluded.
Dr. Smolen has been a consultant to several drug companies. Dr. Ramiro has been a consultant to or speaker on behalf of AbbVie, Eli Lilly, Merck, Novartis, and Sanofi, and she has received research funding from Merck. Dr. Siebert has been a consultant to or speaker on behalf of AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, and UCB, and he has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
REPORTING FROM EULAR 2019 CONGRESS
EULAR revises its RA management recommendations
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
MADRID – No change to designating methotrexate the first disease-modifying drug to prescribe, before any biologic drug, and no adoption of imaging criteria to determine whether a patient is in remission.
“Imaging with ultrasound or MRI is out” as a remission criterion. “It’s high risk and a waste of resources,” declared Josef S. Smolen, MD, head of the EULAR writing panel, in the most forceful declaration he made while presenting the pending recommendation revision at the European Congress of Rheumatology.
Dr. Smolen’s strong warning against an imaging parameter when treating RA patients toward a remission target was no surprise, as he had already voiced this opinion in an editorial he coauthored earlier this year (JAMA. 2019 Feb 5;321[5]:457-8). The editorial cited data from three independent studies that compared an RA treatment strategy that used an imaging measure of joint inflammation as a treatment target along with clinical assessment against clinical assessment alone. All three studies found no benefit from ultrasound or MRI for defining a treatment goal, and two of the studies showed evidence for harm. “Using imaging to guide therapy led to prescription of potentially harmful medicines without differences in the primary outcomes, but at high costs and potential burden of unnecessary treatment changes and risks for patients,” noted Dr. Smolen and his coauthor in the editorial.
The report that this editorial addressed (JAMA. 2019 Feb 5;321[5]:461-72) also provided some of the most recent evidence for the second omission from the new revision that Dr. Smolen called out: No change to the recommendation to use methotrexate as initial treatment for any RA patient. “We continue to say that methotrexate is the first treatment strategy. There is no new evidence that any biological treatment is better than methotrexate, so there is no change,” said Dr. Smolen, professor of medicine at the Medical University of Vienna, who also led the EULAR writing panel for the immediately preceding set of RA treatment recommendations first unveiled 3 years before (Ann Rheum Dis. 2017 Jun;76[6]:960-77).
Perhaps the most notable changes to the recommendations are the way they handle targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), a class that currently is synonymous with the Janus kinase (JAK) inhibitors. “Because of new evidence we have lifted up the tsDMARDs” so that no preference is given to biologic DMARDs over the ts class as happened in the 2016 version, Dr. Smolen said. Another revision to this recommendation was to change the addition of either a biologic or tsDMARD to a patient not fully responsive to a conventional-synthetic (cs) DMARD and with poor prognostic factors from a “should be considered” to a “should be added” recommendation.
Another way in which the pending revision uplifted tsDMARDs was in the wording for the recommendation that deals with patients who do not respond to a first tumor necrosis factor (TNF) inhibitor plus methotrexate or another csDMARD, and now lists as the first option switching to a biologic or tsDMARD with a different mode of action followed by a different TNF inhibitor, a reversal of order from before when a different TNF inhibitor got first mention. This order change was a modest revision that reflected observational evidence that was modestly persuasive that switching to an agent with a different mechanism of action is often the most effective approach, Dr. Smolen said.
The new recommendations also reaffirmed the eleventh recommendation from the 2016 version, which called for tapering of the biologic or tsDMARD from a patient in remission while retaining the csDMARD, usually methotrexate. Dr. Smolen cited new evidence in favor of this approach (Ann Rheum Dis. 2019 Jun;78[6]:746-53), which allowed the writing panel to upgrade the evidence supporting this recommendation to the A level. The concept of tapering down the biologic or tsDMARD for a patient in sustained remission while maintaining the csDMARD was “fully confirmed” in a recent report, he added. The writing panel also upticked its rating of the evidence in favor of cautiously tapering the csDMARD in patients who maintain remission on just a csDMARD.
One final element in the pending revision called out a newly identified safety signal, an increased risk for venous thromboembolism among patients on certain high dosages of JAK inhibitors, especially in patients with increased risk for venous thromboembolism. This new safety concern adds to the already-described increased risk for herpes zoster from JAK inhibitors, especially in Japanese and Korean populations, Dr. Smolen said. In general, more long-term safety data for JAK inhibitors are needed.
The draft update also added one new overarching principle: “Patients require access to multiple drugs with different modes of action to address the heterogeneity of RA, and patients may require multiple, successive treatments throughout life.” Overall, pending changes to the RA recommendations were limited because “the EULAR recommendations have achieved a steady state of the art” for defining whom to treat, treatment targets, and appropriate treatment strategies, Dr. Smolen said.
Dr. Smolen had been a consultant to or a speaker on behalf of several drug companies.
EXPERT ANALYSIS FROM EULAR 2019 CONGRESS
Ultra low-dose rituximab retains promise in rheumatoid arthritis
MADRID – Retreatment of rheumatoid arthritis (RA) with an ultra low-dose of rituximab failed to meet the predefined noninferiority endpoint relative to a higher dose in a double-blind randomized trial, but the investigators still think this strategy may be viable in selected patients.
Lise M. Verhoef, MSc, a researcher in rheumatology at the Sint Maartenskliniek in Nijmegen, the Netherlands, who presented the data as a late-breaker at the European Congress of Rheumatology, explains in a video interview why the negative trial still might support an ultra low-dose strategy.
This trial, called REDO, was conceived after it was observed that most patients with RA are well controlled on a single injection of 1,000 mg of rituximab even though this is half the standard dose of two 1,000 mg doses given 15 days apart. The study was designed to determine whether even lower doses could be used.
The study enrolled 142 patients with RA who were being retreated with rituximab after responding previously to this therapy. In a 1:2:2 ratio, patients were randomized to single rituximab injections of 1,000 mg, 500 mg, or 200 mg. Outcome then were compared at the end of 6 months.
Noninferiority was defined as 0.5 difference in DAS28-CRP score (disease activity score using C-reactive protein instead of erythrocyte sedimentation rate) score adjusted for baseline disease status and use of conventional disease-modifying antirheumatic drugs (DMARDs).
Although noninferior at 3 months, the 500 mg dose did not meet the noninferiority criteria at 6 months. Due to a hierarchical design, evaluation of the 200 mg dose was precluded by the negative result with the 500 mg dose.
However, the majority of patients did respond to both the 500 mg and 200 mg dose. The failure to meet noninferiority was due to a limited number of patients who required rescue therapy for a flare. As a result, the investigators believe a trial of ultra low-dose therapy still might be reasonable.
In this interview, Ms. Verhoef explains that at her center patients who are well controlled on a 1,000 mg dose of rituximab now are being offered a 500 mg dose for retreatment. If they continue to respond, further retreatment with a 200 mg dose is considered.
Ms. Verhoef had no relevant financial disclosures.
MADRID – Retreatment of rheumatoid arthritis (RA) with an ultra low-dose of rituximab failed to meet the predefined noninferiority endpoint relative to a higher dose in a double-blind randomized trial, but the investigators still think this strategy may be viable in selected patients.
Lise M. Verhoef, MSc, a researcher in rheumatology at the Sint Maartenskliniek in Nijmegen, the Netherlands, who presented the data as a late-breaker at the European Congress of Rheumatology, explains in a video interview why the negative trial still might support an ultra low-dose strategy.
This trial, called REDO, was conceived after it was observed that most patients with RA are well controlled on a single injection of 1,000 mg of rituximab even though this is half the standard dose of two 1,000 mg doses given 15 days apart. The study was designed to determine whether even lower doses could be used.
The study enrolled 142 patients with RA who were being retreated with rituximab after responding previously to this therapy. In a 1:2:2 ratio, patients were randomized to single rituximab injections of 1,000 mg, 500 mg, or 200 mg. Outcome then were compared at the end of 6 months.
Noninferiority was defined as 0.5 difference in DAS28-CRP score (disease activity score using C-reactive protein instead of erythrocyte sedimentation rate) score adjusted for baseline disease status and use of conventional disease-modifying antirheumatic drugs (DMARDs).
Although noninferior at 3 months, the 500 mg dose did not meet the noninferiority criteria at 6 months. Due to a hierarchical design, evaluation of the 200 mg dose was precluded by the negative result with the 500 mg dose.
However, the majority of patients did respond to both the 500 mg and 200 mg dose. The failure to meet noninferiority was due to a limited number of patients who required rescue therapy for a flare. As a result, the investigators believe a trial of ultra low-dose therapy still might be reasonable.
In this interview, Ms. Verhoef explains that at her center patients who are well controlled on a 1,000 mg dose of rituximab now are being offered a 500 mg dose for retreatment. If they continue to respond, further retreatment with a 200 mg dose is considered.
Ms. Verhoef had no relevant financial disclosures.
MADRID – Retreatment of rheumatoid arthritis (RA) with an ultra low-dose of rituximab failed to meet the predefined noninferiority endpoint relative to a higher dose in a double-blind randomized trial, but the investigators still think this strategy may be viable in selected patients.
Lise M. Verhoef, MSc, a researcher in rheumatology at the Sint Maartenskliniek in Nijmegen, the Netherlands, who presented the data as a late-breaker at the European Congress of Rheumatology, explains in a video interview why the negative trial still might support an ultra low-dose strategy.
This trial, called REDO, was conceived after it was observed that most patients with RA are well controlled on a single injection of 1,000 mg of rituximab even though this is half the standard dose of two 1,000 mg doses given 15 days apart. The study was designed to determine whether even lower doses could be used.
The study enrolled 142 patients with RA who were being retreated with rituximab after responding previously to this therapy. In a 1:2:2 ratio, patients were randomized to single rituximab injections of 1,000 mg, 500 mg, or 200 mg. Outcome then were compared at the end of 6 months.
Noninferiority was defined as 0.5 difference in DAS28-CRP score (disease activity score using C-reactive protein instead of erythrocyte sedimentation rate) score adjusted for baseline disease status and use of conventional disease-modifying antirheumatic drugs (DMARDs).
Although noninferior at 3 months, the 500 mg dose did not meet the noninferiority criteria at 6 months. Due to a hierarchical design, evaluation of the 200 mg dose was precluded by the negative result with the 500 mg dose.
However, the majority of patients did respond to both the 500 mg and 200 mg dose. The failure to meet noninferiority was due to a limited number of patients who required rescue therapy for a flare. As a result, the investigators believe a trial of ultra low-dose therapy still might be reasonable.
In this interview, Ms. Verhoef explains that at her center patients who are well controlled on a 1,000 mg dose of rituximab now are being offered a 500 mg dose for retreatment. If they continue to respond, further retreatment with a 200 mg dose is considered.
Ms. Verhoef had no relevant financial disclosures.
REPORTING FROM EULAR 2019 Congress
Video program engages patients in treat-to-target concept
MADRID – according to data generated from a randomized trial.
One of the major goals of the video program is to inform patients about the treat-to-target concept of RA management, explained Maria I. Danila, MD, a rheumatologist at the University of Alabama at Birmingham.
Although physicians know this to be a guiding tenet for RA management, she explains in this video interview that 50% or more of patients are unaware of this therapeutic goal.
For patients who resist treatment escalation for fear of side effects, this lack of awareness might provide one explanation for failing to adhere to guideline-recommended therapy, Dr. Danila said at the European Congress of Rheumatology. She believes that patients need more information about the potential for treatment escalation to improve function.
To address this issue, a short video was developed to explain the treat-to-target concept. It was then tested in a randomized trial. Those who viewed the video expressed greater willingness to change intervention on the advice of their rheumatologist relative to those who did not (P = 0.01).
Further studies are planned, including studies to test whether willingness to escalate treatment results in better outcomes and whether linking patient behavioral goals such as being able to play golf again will enhance treatment adherence. Dr. Danila envisions wide distribution of this video if further studies demonstrate that it helps patients cooperate with treatment escalation when needed.
Dr. Danila received research support from Pfizer.
MADRID – according to data generated from a randomized trial.
One of the major goals of the video program is to inform patients about the treat-to-target concept of RA management, explained Maria I. Danila, MD, a rheumatologist at the University of Alabama at Birmingham.
Although physicians know this to be a guiding tenet for RA management, she explains in this video interview that 50% or more of patients are unaware of this therapeutic goal.
For patients who resist treatment escalation for fear of side effects, this lack of awareness might provide one explanation for failing to adhere to guideline-recommended therapy, Dr. Danila said at the European Congress of Rheumatology. She believes that patients need more information about the potential for treatment escalation to improve function.
To address this issue, a short video was developed to explain the treat-to-target concept. It was then tested in a randomized trial. Those who viewed the video expressed greater willingness to change intervention on the advice of their rheumatologist relative to those who did not (P = 0.01).
Further studies are planned, including studies to test whether willingness to escalate treatment results in better outcomes and whether linking patient behavioral goals such as being able to play golf again will enhance treatment adherence. Dr. Danila envisions wide distribution of this video if further studies demonstrate that it helps patients cooperate with treatment escalation when needed.
Dr. Danila received research support from Pfizer.
MADRID – according to data generated from a randomized trial.
One of the major goals of the video program is to inform patients about the treat-to-target concept of RA management, explained Maria I. Danila, MD, a rheumatologist at the University of Alabama at Birmingham.
Although physicians know this to be a guiding tenet for RA management, she explains in this video interview that 50% or more of patients are unaware of this therapeutic goal.
For patients who resist treatment escalation for fear of side effects, this lack of awareness might provide one explanation for failing to adhere to guideline-recommended therapy, Dr. Danila said at the European Congress of Rheumatology. She believes that patients need more information about the potential for treatment escalation to improve function.
To address this issue, a short video was developed to explain the treat-to-target concept. It was then tested in a randomized trial. Those who viewed the video expressed greater willingness to change intervention on the advice of their rheumatologist relative to those who did not (P = 0.01).
Further studies are planned, including studies to test whether willingness to escalate treatment results in better outcomes and whether linking patient behavioral goals such as being able to play golf again will enhance treatment adherence. Dr. Danila envisions wide distribution of this video if further studies demonstrate that it helps patients cooperate with treatment escalation when needed.
Dr. Danila received research support from Pfizer.
REPORTING FROM EULAR 2019 Congress
Cardiovascular events in U.S. RA patients fall to non-RA level
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
MADRID – U.S. patients with rheumatoid arthritis stopped having an excess of cardiovascular disease events during the 2000s.
During both the 1980s and 1990s, patients with rheumatoid arthritis (RA) residing in a 27-county region in southeastern Minnesota and northwestern Wisconsin had cardiovascular disease event rates that were more than twice the rates in similar adults without RA, but that changed during the 2000s, Elena Myasoedova, MD, said in a poster she presented at the European Congress of Rheumatology. During 2000-2009, RA patients enrolled in the Rochester (Minn.) Epidemiology Project had an incidence of cardiovascular disease events at a rate that was 12% lower, compared with matched adults without RA who were also enrolled in the same regional database, reported Dr. Myasoedova, a rheumatologist at the Mayo Clinic in Rochester, and her associates.
“We hypothesize that improved management of RA, including implementation of a treat-to-target strategy and the introduction of biological drugs could have influenced this, as well as increased awareness of and improved prevention of cardiovascular disease,” Dr. Myasoedova said in an interview. The findings “give us a hint that tight control of RA disease activity is also likely to help cardiovascular disease burden.”
She and her associates identified 906 people enrolled in the Rochester Epidemiology Project who had incident RA based on the 1987 criteria of the American College of Rheumatology and matched them by age, sex, and index year with 905 people in the registry without RA. These cohorts included roughly 200 people from each subgroup tracked during the 1980s, 300 from each subgroup tracked during the 1990s, and about 400 in each subgroup tracked during the 2000s. They averaged about 56 years old, and about two-thirds were women.
During the 1980s, the cumulative incidence of nonfatal MI, nonfatal stroke, or cardiovascular disease (CVD) death was 2.11-fold more common among the RA patients than in the matched controls without RA, and during the 1990s this ratio showed a 2.13-fold excess of CVD events among the RA patients. The between-group differences in both decades were statistically significant. During the 2000s, the RA patients actually had a nominally lower rate of CVD events, at 0.88 times the rate of the controls, a difference that was not statistically significant.
Dr. Myasoedova and her associates had previously reported a similar finding in an analysis that used a smaller number of people and focused exclusively on rates of CVD (J Rheumatol. 2017 Jun;44[6]:732-9).
A few factors limit the generalizability of the finding, Dr. Myasoedova cautioned. First, the population studied was about 90% white. Also, people in the Rochester Epidemiology Project receive their medical care from clinicians at the Mayo Clinic or an affiliated hospital in the region covered by the Project.
“These data are from a large, tertiary care center,” and so the findings are most directly applicable to patients who receive medical care in a similar setting that provides guideline-directed management of both RA and CVD risk.
A long-standing hypothesis is that CVD has an inflammatory component. These data support that concept by suggesting that when inflammatory disease is well controlled in RA patients, their CVD risk drops, Dr. Myasoedova said. “CVD has been seen as the number one comorbidity for RA patients, and it remains that way, but it’s very reassuring that the CVD rate has improved. It shows we’re doing something right.”
The study received no commercial funding. Dr. Myasoedova had no relevant disclosures.
SOURCE: Myasoedova E et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):1024-5. Abstract FRI0654. DOI: 10.1136/annrheumdis-2019-eular.4996.
REPORTING FROM EULAR 2019 CONGRESS
EULAR issues guidelines on managing rheumatic complications of cancer immunotherapies
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
REPORTING FROM EULAR 2019 CONGRESS