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Updated consensus statement assesses new migraine treatments
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
FROM HEADACHE
Three new ACR guidelines recommend treatment for six forms of vasculitis
Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.
“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”
The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.
To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).
As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
GCA and TAK guideline
Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.
For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”
“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.
These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”
“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”
Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.
“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.
“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”
For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
AAV guideline
Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”
One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.
“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”
Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.
“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”
And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”
“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”
PAN guideline
Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.
According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.
The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.
Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.
“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”
The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.
To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).
As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
GCA and TAK guideline
Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.
For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”
“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.
These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”
“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”
Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.
“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.
“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”
For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
AAV guideline
Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”
One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.
“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”
Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.
“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”
And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”
“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”
PAN guideline
Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.
According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.
The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.
Three new guidelines from the American College of Rheumatology, in partnership with the Vasculitis Foundation, offer evidence-based recommendations for managing and treating six different forms of systemic vasculitis.
“It’s not unusual for many rheumatologists to have fairly limited experience caring for patients with vasculitis,” coauthor Sharon Chung, MD, director of the Vasculitis Clinic at the University of California, San Francisco, said in an interview. “And with limited experience comes anxiety and concerns about whether or not one is treating patients appropriately. First and foremost, these guidelines are to help rheumatologists who may not have experience treating patients with vasculitides, to provide them with a framework they can use.”
The guidelines – the first to be produced and endorsed by both the ACR and the Vasculitis Foundation – were published July 8 in both Arthritis & Rheumatology and Arthritis Care & Research.
To assess the recent expansion in diagnostic and treatment options for various forms of vasculitis, the ACR assembled a literature review team, an 11-person patient panel, and a voting panel – made up of 9 adult rheumatologists, 5 pediatric rheumatologists, and 2 patients – to evaluate evidence, provide feedback, and formulate and vote on recommendations, respectively. The guidelines cover six types of vasculitis: one focusing on giant cell arteritis (GCA) and Takayasu arteritis (TAK); one on polyarteritis nodosa (PAN), and another on three forms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).
As with other ACR guidelines, these three were developed via the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which was used to rate the quality of the gathered evidence. For a recommendation to be published, it required 70% consensus or greater from the voting panel.
GCA and TAK guideline
Regarding the management and treatment of GCA and TAK, the guideline offers 42 recommendations and three ungraded position statements. Due to the low quality of evidence – “reflecting the paucity of randomized clinical trials in these diseases,” the authors noted – only one of the GCA recommendations and one of the TAK recommendations are strong; the rest are conditional.
For patients with GCA, the guideline strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other notable recommendations include favoring oral glucocorticoids (GCs) with tocilizumab (Actemra) over oral glucocorticoids alone in newly diagnosed GCA, adding a non-GC immunosuppressive agent to oral GCs for GCA patients with active extracranial large vessel involvement, and preferring temporary artery biopsy as their “diagnostic test of choice at this time.”
“The Europeans generally are more comfortable relying on temporal artery ultrasound,” Robert F. Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York, said in an interview. “In this country, possibly in part due to less uniform expertise in performing these ultrasounds, we have not had as much success in terms of accuracy.
These ACR guidelines therefore recommended biopsy to establish the diagnosis in patients with cranial presentations, whereas in the EULAR guidelines, ultrasound was felt to be preferable to biopsy.”
“While we have temporal artery ultrasound available in the United States, we just don’t have the expertise at this point to perform or interpret that test like the European rheumatologists do,” Dr. Chung agreed. “But I think we’re all hopeful that experience with temporal artery ultrasound will improve in the future, so we can use that test instead of an invasive biopsy.”
Dr. Spiera, who was not a coauthor on any of the guidelines, also highlighted the conditional recommendation of noninvasive vascular imaging of the large vessels in patients with newly diagnosed GCA.
“It is well recognized that a substantial portion of patients with GCA have unrecognized evidence of large vessel involvement, and patients with GCA in general are at higher risk of aneurysms later in the disease course,” he said. “These guidelines suggest screening even patients with purely cranial presentations for large vessel involvement with imaging to possibly identify the patients at higher risk for those later complications.
“What they didn’t offer were recommendations on how to follow up on that imaging,” he added, “which is an important and as-yet-unanswered question.”
For patients with TAK, the guideline again strongly recommends long-term clinical monitoring over no clinical monitoring for anyone in apparent clinical remission. Other conditional recommendations include choosing a non-GC immunosuppressive agent such as methotrexate or a tumor necrosis factor (TNF) inhibitor over tocilizumab as initial therapy because “the efficacy of tocilizumab in TAK is not established at this time.”
AAV guideline
Regarding the management and treatment of GPA, MPA, and EGPA, the guideline offers 41 recommendations and 10 ungraded position statements. All recommendations were conditional, and many address GPA and MPA together because, as the authors noted, “pivotal trials have enrolled both groups and presented results for these diseases together.”
One notable recommendation is their preference for rituximab over cyclophosphamide for remission induction and for rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA or MPA. “I don’t think this is a surprise to people, but I think it reaffirms where our current practice is moving,” Dr. Chung said.
“The literature supports that in patients with relapsing disease, rituximab works better than cyclophosphamide for remission induction,” Dr. Spiera said. “But in these guidelines, even in new disease, rituximab is suggested as the agent of choice to induce remission. I would say that that is reasonable, but you could make an argument that it’s maybe beyond what the literature supports, particularly in patients with advanced renal insufficiency attributable to that initial vasculitis flare.”
Other recommendations include being against routinely adding plasma exchange to remission induction therapy in GPA or MPA patients with active glomerulonephritis – although they added that it should be considered in patients at high risk of end-stage kidney disease – as well as preferring cyclophosphamide or rituximab over mepolizumab for remission induction in patients with severe EGPA.
“We, to the surprise of many, were more supportive for the use of rituximab in EGPA than others were expecting, given the limited evidence,” Dr. Chung said. “One of the reasons for that is the wide experience we’ve had with rituximab in GPA and MPA, and our recognition that there is a population of patients with EGPA who are ANCA positive who do seem to benefit from rituximab therapy.”
And although the voting panel strongly favored treatment with methotrexate or azathioprine over trimethoprim/sulfamethoxazole for GPA patients in remission, they ultimately labeled the recommendation as conditional “due to the lack of sufficient high-quality evidence comparing the two treatments.”
“There has been progress in terms of well-done clinical trials to inform our decision-making, particularly for ANCA-associated vasculitis, both in terms of how to induce and maintain remission,” Dr. Spiera said. “Though the recommendations were conditional, I think there’s very strong data to support many of them.”
PAN guideline
Regarding the management and treatment of PAN, the guideline offers 16 recommendations – all but one are conditional – and one ungraded position statement. Their strong recommendation was for treatment with TNF inhibitors over GCs in patients with clinical manifestations of deficiency of adenosine deaminase 2, which they asked doctors to consider “in the setting of a PAN-like syndrome with strokes.” Other conditional recommendations include treating patients with newly diagnosed, severe PAN with cyclophosphamide and GCs, as well as the use of abdominal vascular imaging and/or a deep-skin biopsy to help establish a diagnosis.
According to the authors, a fourth guideline on treating and managing Kawasaki syndrome will be released in the coming weeks.
The guidelines were supported by the ACR and the Vasculitis Foundation. Several authors acknowledged potential conflicts of interest, including receiving speaking and consulting fees, research grants, and honoraria from various pharmaceutical companies. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, InflaRx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen.
FROM ARTHRITIS & RHEUMATOLOGY
New ACR guidance recommends COVID-19 vaccination in RMD patients
Newly updated COVID-19 vaccination guidance from the American College of Rheumatology offers detailed insight into how clinicians should proceed with use, timing, and prioritization of COVID-19 vaccines in patients with rheumatic and musculoskeletal diseases (RMDs).
“The task force advised health care providers to avoid being overly dogmatic in following these recommendations,” Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and colleagues wrote. “The attempt to optimize vaccine response in relation to the use and timing of immunosuppressive medications should not compromise a willing patient’s ability to undergo vaccination in a timely manner and risk a missed vaccination opportunity.” The guidelines were published in Arthritis & Rheumatology.
To review the published literature and determine the safety and efficacy of the available COVID-19 vaccines for patients with RMDs, a task force made up of nine rheumatologists/immunologists, two infectious disease specialists, and two public health physicians was formed. The ACR COVID-19 Vaccine Guidance Task Force considered vaccine clinical trial data and overall COVID-19 risk and outcomes among RMD patients, along with the immunogenicity of other vaccines in patients on immunomodulatory therapies and the safety profile of non-COVID vaccines in RMD patients.
Using a 9-point numeric scoring system, the task force developed 74 draft guidance statements that were rated with a median score of 7, 8, or 9. Consensus was deemed strong for 16 of the statements and moderate for the remaining 58.
Of the general considerations related to COVID-19 vaccination, the only statement to achieve strong consensus called for the rheumatology health care provider to take responsibility for assessing their patients’ COVID-19 vaccination status. Other notable statements asserted that patients with autoimmune inflammatory rheumatic diseases (AIIRDs) are at higher risk for hospitalized COVID-19, compared with the general population, and should be prioritized for vaccination accordingly, even though a risk for disease flare or worsening exists and the expected vaccine response for patients on systemic immunomodulatory therapies is “likely to be blunted in its magnitude and duration.”
Takeaway advice
When asked about a top-line takeaway for rheumatologists, Dr. Curtis replied: “Make sure that your patients are getting vaccinated. Even though the vaccine in patients with compromised immune systems might not work quite as well and might not last quite as long, they still should get vaccinated. And vaccine hesitancy is a real thing.”
Citing unpublished survey data, he estimated that roughly 25% of people with rheumatic conditions remain unvaccinated, and more than half of them said they had no vaccination plans. “That’s a pretty important message when up to a quarter of your higher-risk people take a pass,” he said. “You’d expect it to be better in people at risk who are on steroids or immune medications. That’s something rheumatologists can help with the most.”
Regarding vaccine use, the task force strongly recommended that RMD patients be offered COVID-19 vaccinations consistent with the emergency use authorization’s current age restrictions and/or Food and Drug Administration approval. They also strongly recommended patients with AIIRDs receive the second dose of a multidose vaccine, even if the first dose led to nonserious adverse events, and that health care providers avoid ordering lab testing to assess COVID-19 immunity in vaccinated and unvaccinated patients.
The issues around testing for immunity are ample, Dr. Curtis said. For starters, “there are different antibodies, and one of them wouldn’t be expected to go up after vaccination.” And even if you are testing for the correct antibodies, “now I get a number. Is my number high enough that says that I’m protected? That’s what clinicians want, that’s what patients want. Unfortunately, we don’t have that test. There’s an antibody test; you can test against the spike protein and get a number, but whether that number has clinical relevance that says you’re protected, and how much, and for how long, we definitely don’t have that information. You could be falsely reassured or falsely alarmed by the results.”
This statement, he added, has been particularly divisive. “A bunch of rheumatologists have said to me: ‘Look, we’re doing this routinely for our patients.’ My rejoinder was: ‘That’s great to know; what’s the evidence base for what you’re doing there? Because I haven’t read that paper.’ I fully acknowledge that, in groups of patients on certain therapies, the antibody response seems somewhat lower. But doctors don’t treat groups of patients; we treat patients one at a time. And I want to know how to help the patient in front of me, and I want to know what to tell him or her if I get the results of an antibody test.”
Finally, the task force emphasized that all AIIRD patients should receive the COVID-19 vaccinations, exempting only those with life-threatening disease, and they stated no preference for one COVID-19 vaccine over the other.
Vaccine choice
“Should you prefer one vaccine or vaccine platform to another? That’s been incredibly controversial,” Dr. Curtis said. Though the efficacy of the mRNA vaccines is often cited at 90%, compared with the roughly 60%-70% efficacy of the Johnson and & Johnson single-dose vaccine, “they’re not head-to-head studies. They weren’t done in the same countries; they weren’t done with the same viral variants. They’re not being evaluated under similar conditions; it’s not fair to hold them up and say: ‘Apples to apples, this one is better than that one.’ ”
“On the other hand,” he added, “if you were choosing, which would you want? If you are given a choice, you’re probably going to have a preference. The downside for a public health group – this group, which is trying to help rheumatologists and their patients make prudent decisions in light of very imperfect and evolving evidence – is that most people don’t have a choice. So if you send the message that one vaccine might be better than another, if that makes people wait for the one that supposedly might be better, you’ve probably done something bad. They’re delaying for what may be a marginal reason, and some vaccine protection is better than no vaccine protection.”
Regarding vaccination timing in patients who are on immunomodulatory therapies, the task force strongly recommended not delaying or adjusting the timing for anyone on hydroxychloroquine, sulfasalazine, leflunomide, apremilast, or intravenous immunoglobulin. They moderately recommended the same for patients on numerous drugs, including methotrexate, tumor necrosis factor inhibitors, Janus kinase inhibitors, abatacept, and glucocorticoids. Patients on rituximab with a low COVID-19 risk were recommended to schedule their vaccination so that the vaccine series is initiated roughly 4 weeks before their next scheduled rituximab cycle.
Regarding the use and timing of immunomodulatory therapies in relation to vaccination, they strongly recommended no modifications for patients on hydroxychloroquine, apremilast, intravenous immunoglobulin, or glucocorticoids. They also moderately recommended no modifications for patients on numerous drugs, including sulfasalazine, leflunomide, azathioprine, oral cyclophosphamide, and TNF inhibitors.
Regarding limitations, the researchers noted that there is no direct evidence about COVID-19 vaccine safety and efficacy yet in this subset of patients. They also acknowledged that they did not follow the rigorous methodology typically used by the ACR in developing formal clinical practice guidelines, calling it an “expected limitation” given the need to issue timely and potentially lifesaving guidance for the rheumatology community.
The authors acknowledged several potential conflicts of interest, including receiving consulting fees, speaking fees, and research grants from various pharmaceutical companies.
Newly updated COVID-19 vaccination guidance from the American College of Rheumatology offers detailed insight into how clinicians should proceed with use, timing, and prioritization of COVID-19 vaccines in patients with rheumatic and musculoskeletal diseases (RMDs).
“The task force advised health care providers to avoid being overly dogmatic in following these recommendations,” Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and colleagues wrote. “The attempt to optimize vaccine response in relation to the use and timing of immunosuppressive medications should not compromise a willing patient’s ability to undergo vaccination in a timely manner and risk a missed vaccination opportunity.” The guidelines were published in Arthritis & Rheumatology.
To review the published literature and determine the safety and efficacy of the available COVID-19 vaccines for patients with RMDs, a task force made up of nine rheumatologists/immunologists, two infectious disease specialists, and two public health physicians was formed. The ACR COVID-19 Vaccine Guidance Task Force considered vaccine clinical trial data and overall COVID-19 risk and outcomes among RMD patients, along with the immunogenicity of other vaccines in patients on immunomodulatory therapies and the safety profile of non-COVID vaccines in RMD patients.
Using a 9-point numeric scoring system, the task force developed 74 draft guidance statements that were rated with a median score of 7, 8, or 9. Consensus was deemed strong for 16 of the statements and moderate for the remaining 58.
Of the general considerations related to COVID-19 vaccination, the only statement to achieve strong consensus called for the rheumatology health care provider to take responsibility for assessing their patients’ COVID-19 vaccination status. Other notable statements asserted that patients with autoimmune inflammatory rheumatic diseases (AIIRDs) are at higher risk for hospitalized COVID-19, compared with the general population, and should be prioritized for vaccination accordingly, even though a risk for disease flare or worsening exists and the expected vaccine response for patients on systemic immunomodulatory therapies is “likely to be blunted in its magnitude and duration.”
Takeaway advice
When asked about a top-line takeaway for rheumatologists, Dr. Curtis replied: “Make sure that your patients are getting vaccinated. Even though the vaccine in patients with compromised immune systems might not work quite as well and might not last quite as long, they still should get vaccinated. And vaccine hesitancy is a real thing.”
Citing unpublished survey data, he estimated that roughly 25% of people with rheumatic conditions remain unvaccinated, and more than half of them said they had no vaccination plans. “That’s a pretty important message when up to a quarter of your higher-risk people take a pass,” he said. “You’d expect it to be better in people at risk who are on steroids or immune medications. That’s something rheumatologists can help with the most.”
Regarding vaccine use, the task force strongly recommended that RMD patients be offered COVID-19 vaccinations consistent with the emergency use authorization’s current age restrictions and/or Food and Drug Administration approval. They also strongly recommended patients with AIIRDs receive the second dose of a multidose vaccine, even if the first dose led to nonserious adverse events, and that health care providers avoid ordering lab testing to assess COVID-19 immunity in vaccinated and unvaccinated patients.
The issues around testing for immunity are ample, Dr. Curtis said. For starters, “there are different antibodies, and one of them wouldn’t be expected to go up after vaccination.” And even if you are testing for the correct antibodies, “now I get a number. Is my number high enough that says that I’m protected? That’s what clinicians want, that’s what patients want. Unfortunately, we don’t have that test. There’s an antibody test; you can test against the spike protein and get a number, but whether that number has clinical relevance that says you’re protected, and how much, and for how long, we definitely don’t have that information. You could be falsely reassured or falsely alarmed by the results.”
This statement, he added, has been particularly divisive. “A bunch of rheumatologists have said to me: ‘Look, we’re doing this routinely for our patients.’ My rejoinder was: ‘That’s great to know; what’s the evidence base for what you’re doing there? Because I haven’t read that paper.’ I fully acknowledge that, in groups of patients on certain therapies, the antibody response seems somewhat lower. But doctors don’t treat groups of patients; we treat patients one at a time. And I want to know how to help the patient in front of me, and I want to know what to tell him or her if I get the results of an antibody test.”
Finally, the task force emphasized that all AIIRD patients should receive the COVID-19 vaccinations, exempting only those with life-threatening disease, and they stated no preference for one COVID-19 vaccine over the other.
Vaccine choice
“Should you prefer one vaccine or vaccine platform to another? That’s been incredibly controversial,” Dr. Curtis said. Though the efficacy of the mRNA vaccines is often cited at 90%, compared with the roughly 60%-70% efficacy of the Johnson and & Johnson single-dose vaccine, “they’re not head-to-head studies. They weren’t done in the same countries; they weren’t done with the same viral variants. They’re not being evaluated under similar conditions; it’s not fair to hold them up and say: ‘Apples to apples, this one is better than that one.’ ”
“On the other hand,” he added, “if you were choosing, which would you want? If you are given a choice, you’re probably going to have a preference. The downside for a public health group – this group, which is trying to help rheumatologists and their patients make prudent decisions in light of very imperfect and evolving evidence – is that most people don’t have a choice. So if you send the message that one vaccine might be better than another, if that makes people wait for the one that supposedly might be better, you’ve probably done something bad. They’re delaying for what may be a marginal reason, and some vaccine protection is better than no vaccine protection.”
Regarding vaccination timing in patients who are on immunomodulatory therapies, the task force strongly recommended not delaying or adjusting the timing for anyone on hydroxychloroquine, sulfasalazine, leflunomide, apremilast, or intravenous immunoglobulin. They moderately recommended the same for patients on numerous drugs, including methotrexate, tumor necrosis factor inhibitors, Janus kinase inhibitors, abatacept, and glucocorticoids. Patients on rituximab with a low COVID-19 risk were recommended to schedule their vaccination so that the vaccine series is initiated roughly 4 weeks before their next scheduled rituximab cycle.
Regarding the use and timing of immunomodulatory therapies in relation to vaccination, they strongly recommended no modifications for patients on hydroxychloroquine, apremilast, intravenous immunoglobulin, or glucocorticoids. They also moderately recommended no modifications for patients on numerous drugs, including sulfasalazine, leflunomide, azathioprine, oral cyclophosphamide, and TNF inhibitors.
Regarding limitations, the researchers noted that there is no direct evidence about COVID-19 vaccine safety and efficacy yet in this subset of patients. They also acknowledged that they did not follow the rigorous methodology typically used by the ACR in developing formal clinical practice guidelines, calling it an “expected limitation” given the need to issue timely and potentially lifesaving guidance for the rheumatology community.
The authors acknowledged several potential conflicts of interest, including receiving consulting fees, speaking fees, and research grants from various pharmaceutical companies.
Newly updated COVID-19 vaccination guidance from the American College of Rheumatology offers detailed insight into how clinicians should proceed with use, timing, and prioritization of COVID-19 vaccines in patients with rheumatic and musculoskeletal diseases (RMDs).
“The task force advised health care providers to avoid being overly dogmatic in following these recommendations,” Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and colleagues wrote. “The attempt to optimize vaccine response in relation to the use and timing of immunosuppressive medications should not compromise a willing patient’s ability to undergo vaccination in a timely manner and risk a missed vaccination opportunity.” The guidelines were published in Arthritis & Rheumatology.
To review the published literature and determine the safety and efficacy of the available COVID-19 vaccines for patients with RMDs, a task force made up of nine rheumatologists/immunologists, two infectious disease specialists, and two public health physicians was formed. The ACR COVID-19 Vaccine Guidance Task Force considered vaccine clinical trial data and overall COVID-19 risk and outcomes among RMD patients, along with the immunogenicity of other vaccines in patients on immunomodulatory therapies and the safety profile of non-COVID vaccines in RMD patients.
Using a 9-point numeric scoring system, the task force developed 74 draft guidance statements that were rated with a median score of 7, 8, or 9. Consensus was deemed strong for 16 of the statements and moderate for the remaining 58.
Of the general considerations related to COVID-19 vaccination, the only statement to achieve strong consensus called for the rheumatology health care provider to take responsibility for assessing their patients’ COVID-19 vaccination status. Other notable statements asserted that patients with autoimmune inflammatory rheumatic diseases (AIIRDs) are at higher risk for hospitalized COVID-19, compared with the general population, and should be prioritized for vaccination accordingly, even though a risk for disease flare or worsening exists and the expected vaccine response for patients on systemic immunomodulatory therapies is “likely to be blunted in its magnitude and duration.”
Takeaway advice
When asked about a top-line takeaway for rheumatologists, Dr. Curtis replied: “Make sure that your patients are getting vaccinated. Even though the vaccine in patients with compromised immune systems might not work quite as well and might not last quite as long, they still should get vaccinated. And vaccine hesitancy is a real thing.”
Citing unpublished survey data, he estimated that roughly 25% of people with rheumatic conditions remain unvaccinated, and more than half of them said they had no vaccination plans. “That’s a pretty important message when up to a quarter of your higher-risk people take a pass,” he said. “You’d expect it to be better in people at risk who are on steroids or immune medications. That’s something rheumatologists can help with the most.”
Regarding vaccine use, the task force strongly recommended that RMD patients be offered COVID-19 vaccinations consistent with the emergency use authorization’s current age restrictions and/or Food and Drug Administration approval. They also strongly recommended patients with AIIRDs receive the second dose of a multidose vaccine, even if the first dose led to nonserious adverse events, and that health care providers avoid ordering lab testing to assess COVID-19 immunity in vaccinated and unvaccinated patients.
The issues around testing for immunity are ample, Dr. Curtis said. For starters, “there are different antibodies, and one of them wouldn’t be expected to go up after vaccination.” And even if you are testing for the correct antibodies, “now I get a number. Is my number high enough that says that I’m protected? That’s what clinicians want, that’s what patients want. Unfortunately, we don’t have that test. There’s an antibody test; you can test against the spike protein and get a number, but whether that number has clinical relevance that says you’re protected, and how much, and for how long, we definitely don’t have that information. You could be falsely reassured or falsely alarmed by the results.”
This statement, he added, has been particularly divisive. “A bunch of rheumatologists have said to me: ‘Look, we’re doing this routinely for our patients.’ My rejoinder was: ‘That’s great to know; what’s the evidence base for what you’re doing there? Because I haven’t read that paper.’ I fully acknowledge that, in groups of patients on certain therapies, the antibody response seems somewhat lower. But doctors don’t treat groups of patients; we treat patients one at a time. And I want to know how to help the patient in front of me, and I want to know what to tell him or her if I get the results of an antibody test.”
Finally, the task force emphasized that all AIIRD patients should receive the COVID-19 vaccinations, exempting only those with life-threatening disease, and they stated no preference for one COVID-19 vaccine over the other.
Vaccine choice
“Should you prefer one vaccine or vaccine platform to another? That’s been incredibly controversial,” Dr. Curtis said. Though the efficacy of the mRNA vaccines is often cited at 90%, compared with the roughly 60%-70% efficacy of the Johnson and & Johnson single-dose vaccine, “they’re not head-to-head studies. They weren’t done in the same countries; they weren’t done with the same viral variants. They’re not being evaluated under similar conditions; it’s not fair to hold them up and say: ‘Apples to apples, this one is better than that one.’ ”
“On the other hand,” he added, “if you were choosing, which would you want? If you are given a choice, you’re probably going to have a preference. The downside for a public health group – this group, which is trying to help rheumatologists and their patients make prudent decisions in light of very imperfect and evolving evidence – is that most people don’t have a choice. So if you send the message that one vaccine might be better than another, if that makes people wait for the one that supposedly might be better, you’ve probably done something bad. They’re delaying for what may be a marginal reason, and some vaccine protection is better than no vaccine protection.”
Regarding vaccination timing in patients who are on immunomodulatory therapies, the task force strongly recommended not delaying or adjusting the timing for anyone on hydroxychloroquine, sulfasalazine, leflunomide, apremilast, or intravenous immunoglobulin. They moderately recommended the same for patients on numerous drugs, including methotrexate, tumor necrosis factor inhibitors, Janus kinase inhibitors, abatacept, and glucocorticoids. Patients on rituximab with a low COVID-19 risk were recommended to schedule their vaccination so that the vaccine series is initiated roughly 4 weeks before their next scheduled rituximab cycle.
Regarding the use and timing of immunomodulatory therapies in relation to vaccination, they strongly recommended no modifications for patients on hydroxychloroquine, apremilast, intravenous immunoglobulin, or glucocorticoids. They also moderately recommended no modifications for patients on numerous drugs, including sulfasalazine, leflunomide, azathioprine, oral cyclophosphamide, and TNF inhibitors.
Regarding limitations, the researchers noted that there is no direct evidence about COVID-19 vaccine safety and efficacy yet in this subset of patients. They also acknowledged that they did not follow the rigorous methodology typically used by the ACR in developing formal clinical practice guidelines, calling it an “expected limitation” given the need to issue timely and potentially lifesaving guidance for the rheumatology community.
The authors acknowledged several potential conflicts of interest, including receiving consulting fees, speaking fees, and research grants from various pharmaceutical companies.
FROM ARTHRITIS & RHEUMATOLOGY
Tofacitinib shows mortality benefit in patients with COVID-19 pneumonia
The Janus kinase inhibitor tofacitinib reduces the risk of both death and respiratory failure in hospitalized adults with COVID-19 pneumonia, a new Brazilian study has found.
“Whether the use of JAK inhibitors is superior or additive to other specific immunomodulatory therapies in patients hospitalized with COVID-19 remains to be determined,” Patrícia O. Guimarães, MD, PhD, of the Hospital Israelita Albert Einstein in São Paulo, and coauthors wrote. The study was published in the New England Journal of Medicine.
The results of previous trials that tested JAK inhibitors as therapies for COVID-19 have been mixed. The second iteration of the Adaptive COVID-19 Treatment Trial (ACTT-2) found that a combination treatment of baricitinib and the Food and Drug Administration–authorized remdesivir was superior to remdesivir alone, but ACTT-4 – which compared baricitinib plus remdesivir with dexamethasone plus remdesivir – was stopped for futility in April 2021.
To assess the efficacy and safety of tofacitinib as a potential treatment for COVID-19, the researchers launched a randomized, double-blind trial made up of 289 patients from 15 sites in Brazil. The Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia (STOP-COVID) split its participants into two groups: one (n = 144) received 10 mg of oral tofacitinib twice daily and the other (n = 145) received placebo. Treatment was to be administered for up to 14 days or until hospital discharge. The participants’ mean age was 56 years, and 34.9% were women.
Over 89% of participants received glucocorticoids during hospitalization, a significant increase, compared with ACTT-2’s 12%. Through 28 days, death or respiratory failure occurred in 18.1% of the tofacitinib group and in 29.0% of the placebo group (risk ratio, 0.63; 95% confidence interval, 0.41-0.97; P = .04). Death from any cause occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group (hazard ratio, 0.49; 95% CI, 0.15-1.63). The median number of days that treatment was administered was 5 in the tofacitinib group and 6 in the placebo group, and the median duration of hospital and ICU stays were similar across groups.
On the eight-level National Institute of Allergy and Infectious Diseases ordinal scale of disease severity, the proportional odds of having a worse score with tofacitinib, compared with placebo, was 0.6 (95% CI, 0.36-1.00) at day 14 and 0.54 (95% CI, 0.27-1.06) at day 28. Adverse events occurred in 26.1% of the tofacitinib group and 22.5% of the placebo group, with serious adverse events occurring in 20 patients (14.1%) on tofacitinib and 17 patients (12%) on placebo. Patients on tofacitinib suffered from events like deep vein thrombosis, acute myocardial infarction, ventricular tachycardia, and myocarditis, each of which affected one person, while one placebo patient each suffered from hemorrhagic stroke and cardiogenic shock. The incidence of serious infection was 3.5% in the tofacitinib group and 4.2% in the placebo group.
Timing may be everything
“There is a lot of interest in repurposing a variety of disease-modifying antirheumatic drugs for the treatment of COVID-19, which includes JAK inhibitors,” Zachary S. Wallace, MD, of the rheumatology unit at Massachusetts General Hospital, Boston, said in an interview. “The ACTT-2 data was compelling; it did suggest perhaps a benefit associated with baricitinib for COVID. This study certainly is more compelling.”
“For many people, there is this hyperinflammatory response in COVID-19 that seems to drive a lot of the morbidity and mortality that we see,” he added. “I think we all hypothesize that some of our treatments may be beneficial there. The challenge that we face is figuring out when the best time is to administer these medicines, and whether they need to be administered as part of a cocktail of therapy.”
Along those lines, Dr. Wallace cited a recent study he coauthored in which rheumatoid arthritis patients who were on JAK inhibitors at baseline had worse COVID-19 severity. But he emphasized that, despite their differing findings, the two studies are not irreconcilable.
“What this might speak to is, the timing of your exposure may be really important,” he said. “At the time of your initial infection, you may need certain aspects of your immune system that a JAK inhibitor may interfere with. But when you initiate a JAK inhibitor, once that phase is complete and you’re in this hyperinflammatory phase, you may have more benefit to target and treat the intense inflammation that we observe in patients who have COVID.”
He also offered up another variable potentially in play: different JAK inhibitors having different targets among the JAK receptors. “It may be that targeting specific JAKs is more beneficial when it comes to treating the hyperinflammatory response of COVID-19.”
The trial was sponsored by Pfizer. Several authors acknowledged potential conflicts of interest, including receiving grants and personal fees from Pfizer and various other pharmaceutical companies.
The Janus kinase inhibitor tofacitinib reduces the risk of both death and respiratory failure in hospitalized adults with COVID-19 pneumonia, a new Brazilian study has found.
“Whether the use of JAK inhibitors is superior or additive to other specific immunomodulatory therapies in patients hospitalized with COVID-19 remains to be determined,” Patrícia O. Guimarães, MD, PhD, of the Hospital Israelita Albert Einstein in São Paulo, and coauthors wrote. The study was published in the New England Journal of Medicine.
The results of previous trials that tested JAK inhibitors as therapies for COVID-19 have been mixed. The second iteration of the Adaptive COVID-19 Treatment Trial (ACTT-2) found that a combination treatment of baricitinib and the Food and Drug Administration–authorized remdesivir was superior to remdesivir alone, but ACTT-4 – which compared baricitinib plus remdesivir with dexamethasone plus remdesivir – was stopped for futility in April 2021.
To assess the efficacy and safety of tofacitinib as a potential treatment for COVID-19, the researchers launched a randomized, double-blind trial made up of 289 patients from 15 sites in Brazil. The Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia (STOP-COVID) split its participants into two groups: one (n = 144) received 10 mg of oral tofacitinib twice daily and the other (n = 145) received placebo. Treatment was to be administered for up to 14 days or until hospital discharge. The participants’ mean age was 56 years, and 34.9% were women.
Over 89% of participants received glucocorticoids during hospitalization, a significant increase, compared with ACTT-2’s 12%. Through 28 days, death or respiratory failure occurred in 18.1% of the tofacitinib group and in 29.0% of the placebo group (risk ratio, 0.63; 95% confidence interval, 0.41-0.97; P = .04). Death from any cause occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group (hazard ratio, 0.49; 95% CI, 0.15-1.63). The median number of days that treatment was administered was 5 in the tofacitinib group and 6 in the placebo group, and the median duration of hospital and ICU stays were similar across groups.
On the eight-level National Institute of Allergy and Infectious Diseases ordinal scale of disease severity, the proportional odds of having a worse score with tofacitinib, compared with placebo, was 0.6 (95% CI, 0.36-1.00) at day 14 and 0.54 (95% CI, 0.27-1.06) at day 28. Adverse events occurred in 26.1% of the tofacitinib group and 22.5% of the placebo group, with serious adverse events occurring in 20 patients (14.1%) on tofacitinib and 17 patients (12%) on placebo. Patients on tofacitinib suffered from events like deep vein thrombosis, acute myocardial infarction, ventricular tachycardia, and myocarditis, each of which affected one person, while one placebo patient each suffered from hemorrhagic stroke and cardiogenic shock. The incidence of serious infection was 3.5% in the tofacitinib group and 4.2% in the placebo group.
Timing may be everything
“There is a lot of interest in repurposing a variety of disease-modifying antirheumatic drugs for the treatment of COVID-19, which includes JAK inhibitors,” Zachary S. Wallace, MD, of the rheumatology unit at Massachusetts General Hospital, Boston, said in an interview. “The ACTT-2 data was compelling; it did suggest perhaps a benefit associated with baricitinib for COVID. This study certainly is more compelling.”
“For many people, there is this hyperinflammatory response in COVID-19 that seems to drive a lot of the morbidity and mortality that we see,” he added. “I think we all hypothesize that some of our treatments may be beneficial there. The challenge that we face is figuring out when the best time is to administer these medicines, and whether they need to be administered as part of a cocktail of therapy.”
Along those lines, Dr. Wallace cited a recent study he coauthored in which rheumatoid arthritis patients who were on JAK inhibitors at baseline had worse COVID-19 severity. But he emphasized that, despite their differing findings, the two studies are not irreconcilable.
“What this might speak to is, the timing of your exposure may be really important,” he said. “At the time of your initial infection, you may need certain aspects of your immune system that a JAK inhibitor may interfere with. But when you initiate a JAK inhibitor, once that phase is complete and you’re in this hyperinflammatory phase, you may have more benefit to target and treat the intense inflammation that we observe in patients who have COVID.”
He also offered up another variable potentially in play: different JAK inhibitors having different targets among the JAK receptors. “It may be that targeting specific JAKs is more beneficial when it comes to treating the hyperinflammatory response of COVID-19.”
The trial was sponsored by Pfizer. Several authors acknowledged potential conflicts of interest, including receiving grants and personal fees from Pfizer and various other pharmaceutical companies.
The Janus kinase inhibitor tofacitinib reduces the risk of both death and respiratory failure in hospitalized adults with COVID-19 pneumonia, a new Brazilian study has found.
“Whether the use of JAK inhibitors is superior or additive to other specific immunomodulatory therapies in patients hospitalized with COVID-19 remains to be determined,” Patrícia O. Guimarães, MD, PhD, of the Hospital Israelita Albert Einstein in São Paulo, and coauthors wrote. The study was published in the New England Journal of Medicine.
The results of previous trials that tested JAK inhibitors as therapies for COVID-19 have been mixed. The second iteration of the Adaptive COVID-19 Treatment Trial (ACTT-2) found that a combination treatment of baricitinib and the Food and Drug Administration–authorized remdesivir was superior to remdesivir alone, but ACTT-4 – which compared baricitinib plus remdesivir with dexamethasone plus remdesivir – was stopped for futility in April 2021.
To assess the efficacy and safety of tofacitinib as a potential treatment for COVID-19, the researchers launched a randomized, double-blind trial made up of 289 patients from 15 sites in Brazil. The Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia (STOP-COVID) split its participants into two groups: one (n = 144) received 10 mg of oral tofacitinib twice daily and the other (n = 145) received placebo. Treatment was to be administered for up to 14 days or until hospital discharge. The participants’ mean age was 56 years, and 34.9% were women.
Over 89% of participants received glucocorticoids during hospitalization, a significant increase, compared with ACTT-2’s 12%. Through 28 days, death or respiratory failure occurred in 18.1% of the tofacitinib group and in 29.0% of the placebo group (risk ratio, 0.63; 95% confidence interval, 0.41-0.97; P = .04). Death from any cause occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group (hazard ratio, 0.49; 95% CI, 0.15-1.63). The median number of days that treatment was administered was 5 in the tofacitinib group and 6 in the placebo group, and the median duration of hospital and ICU stays were similar across groups.
On the eight-level National Institute of Allergy and Infectious Diseases ordinal scale of disease severity, the proportional odds of having a worse score with tofacitinib, compared with placebo, was 0.6 (95% CI, 0.36-1.00) at day 14 and 0.54 (95% CI, 0.27-1.06) at day 28. Adverse events occurred in 26.1% of the tofacitinib group and 22.5% of the placebo group, with serious adverse events occurring in 20 patients (14.1%) on tofacitinib and 17 patients (12%) on placebo. Patients on tofacitinib suffered from events like deep vein thrombosis, acute myocardial infarction, ventricular tachycardia, and myocarditis, each of which affected one person, while one placebo patient each suffered from hemorrhagic stroke and cardiogenic shock. The incidence of serious infection was 3.5% in the tofacitinib group and 4.2% in the placebo group.
Timing may be everything
“There is a lot of interest in repurposing a variety of disease-modifying antirheumatic drugs for the treatment of COVID-19, which includes JAK inhibitors,” Zachary S. Wallace, MD, of the rheumatology unit at Massachusetts General Hospital, Boston, said in an interview. “The ACTT-2 data was compelling; it did suggest perhaps a benefit associated with baricitinib for COVID. This study certainly is more compelling.”
“For many people, there is this hyperinflammatory response in COVID-19 that seems to drive a lot of the morbidity and mortality that we see,” he added. “I think we all hypothesize that some of our treatments may be beneficial there. The challenge that we face is figuring out when the best time is to administer these medicines, and whether they need to be administered as part of a cocktail of therapy.”
Along those lines, Dr. Wallace cited a recent study he coauthored in which rheumatoid arthritis patients who were on JAK inhibitors at baseline had worse COVID-19 severity. But he emphasized that, despite their differing findings, the two studies are not irreconcilable.
“What this might speak to is, the timing of your exposure may be really important,” he said. “At the time of your initial infection, you may need certain aspects of your immune system that a JAK inhibitor may interfere with. But when you initiate a JAK inhibitor, once that phase is complete and you’re in this hyperinflammatory phase, you may have more benefit to target and treat the intense inflammation that we observe in patients who have COVID.”
He also offered up another variable potentially in play: different JAK inhibitors having different targets among the JAK receptors. “It may be that targeting specific JAKs is more beneficial when it comes to treating the hyperinflammatory response of COVID-19.”
The trial was sponsored by Pfizer. Several authors acknowledged potential conflicts of interest, including receiving grants and personal fees from Pfizer and various other pharmaceutical companies.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Many comatose TBI patients recover consciousness during rehab
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
FROM JAMA NEUROLOGY
Lower glucocorticoid dose proves effective for new-onset ANCA-associated vasculitis
A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.
“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.
To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m2 per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.
Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).
Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.
End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).
Less glucocorticoids makes sense for subset of patients with milder vasculitis
“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”
She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.
“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.
To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.
“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”
The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.
The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.
A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.
“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.
To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m2 per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.
Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).
Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.
End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).
Less glucocorticoids makes sense for subset of patients with milder vasculitis
“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”
She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.
“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.
To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.
“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”
The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.
The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.
A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.
“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.
To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m2 per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.
Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).
Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.
End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).
Less glucocorticoids makes sense for subset of patients with milder vasculitis
“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”
She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.
“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.
To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.
“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”
The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.
The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.
FROM JAMA
Risk factors identified for late seizure relapse after epilepsy surgery
according to a new study on the factors most associated with seizure recurrence in drug-resistant epilepsy.
“As our study analyzed late seizure relapse, our results are not applicable for short‐term seizure control. Vice versa, results for short‐term outcomes should not be transferred to long‐term outcomes,” Stephan Petrik of the Epilepsy Center at the University of Freiburg (Germany) and colleagues wrote. The study was published in the May 2021 issue of Epilepsia.
To assess the variables that increase risk of late seizure recurrence following surgery, the researchers retrospectively studied the medical records of patients who underwent resective epilepsy surgery at the University Hospital Freiburg (Germany) between 1999 and 2015. Of the 1,278 initial patients, a group of 99 participants (7.7%) with seizure relapses after at least 2 years of complete seizure freedom were matched with controls experiencing long-term seizure freedom. The two groups had similar mean durations of epilepsy from onset to surgery: 13.9 years in the relapse group and 13.0 years in the control group.
The mean follow-up was 9.7 years (standard deviation, 4.0; range, 2.9-18.5) in the relapse group and 8.2 years (SD, 3.5; range, 2.2-18.3) in the control group. The mean time to late seizure recurrence was 56.6 months, and two-thirds of patients relapsed in the 5 years after surgery. Twenty of the relapse patients only experienced a single seizure, and 41% of the patients who reported more than one seizure had a frequency of less than one per month.
The type of resection had no discernible impact on outcomes, although anterior temporal lobe resection did trend toward being associated with recurrence (odds ratio, 2.7; 95% confidence interval, 0.93-8.89; P = .06). Incomplete resection was significantly associated with late relapse but did not seem to affect timing: the mean duration of seizure freedom was 56.5 months with complete resection and 58.5 months with incomplete resection (P = .62). Additional preoperative PET scans were performed on 45% of patients in the relapse group, compared with 29% in the control group.
After multivariate analysis, predictors for late relapse included incomplete resection (OR, 3.81; 95% CI, 1.79-8.53; P < .001); the existence of additional, potentially epileptogenic lesions in the contralateral hemisphere on presurgical MRI (OR, 3.36; 95% CI, 1.18-10.62; P = .03); epilepsy onset during the first year of life (OR, 4.24; 95% CI, 1.4-15.89; P = .02); and preoperative PET scans being performed (OR, 2.47; 95% CI, 1.25-4.97; P = .01). Though use of preoperative and postoperative antiepileptic drugs (AEDs) was higher in the relapse group, along with complete withdrawal being more common in the control group (68%, compared with 51%), neither was deemed significant in multivariate analysis.
What to do about seizure relapse risk factors
“This is one of the best analyses of the factors that contribute to late seizure relapse,” Gregory K. Bergey, MD, director of the Johns Hopkins Epilepsy Center in Baltimore, said in an interview. “Am I surprised by their results? Not necessarily.”
What did jump out, he said, was AED use not being a predictor of recurrence, as well as all the patients with late relapse having lesional epilepsy. “As they point out, you can have relapse with nonlesional epilepsy, but very often it happens in the first year or 2. If someone is 2 years out and doesn’t have a lesion, they’re probably more likely to remain seizure free.”
Despite the researchers’ comprehensive review of risk factors, the question remains: What to do with this information?
“They’ve done a very good job of identifying that 7.7% of 1,200 who are at risk of a late relapse,” he said. “Now, take those patients with high-risk factors and launch a trial where you keep medicines the same or do something that would alter that outcome.”
“The problem is,” he added, “that’s a 10-year study. It’s easy for me to sit here and call for one of those. But still, as valuable as this was, it’s a retrospective study. Now you have to say, what are the implications of this? What can we do in the prospective fashion?”
The authors acknowledged their study’s other limitations, including a lack of information on the reasons for an incomplete resection, a notable decrease in follow-up visits more than 5 years after surgery, and potential selection bias. They added, however, that “matching by age at surgery, gender, and time to relapse/last follow‐up” should have helped reduce any significant bias.
No potential conflicts of interest were disclosed.
according to a new study on the factors most associated with seizure recurrence in drug-resistant epilepsy.
“As our study analyzed late seizure relapse, our results are not applicable for short‐term seizure control. Vice versa, results for short‐term outcomes should not be transferred to long‐term outcomes,” Stephan Petrik of the Epilepsy Center at the University of Freiburg (Germany) and colleagues wrote. The study was published in the May 2021 issue of Epilepsia.
To assess the variables that increase risk of late seizure recurrence following surgery, the researchers retrospectively studied the medical records of patients who underwent resective epilepsy surgery at the University Hospital Freiburg (Germany) between 1999 and 2015. Of the 1,278 initial patients, a group of 99 participants (7.7%) with seizure relapses after at least 2 years of complete seizure freedom were matched with controls experiencing long-term seizure freedom. The two groups had similar mean durations of epilepsy from onset to surgery: 13.9 years in the relapse group and 13.0 years in the control group.
The mean follow-up was 9.7 years (standard deviation, 4.0; range, 2.9-18.5) in the relapse group and 8.2 years (SD, 3.5; range, 2.2-18.3) in the control group. The mean time to late seizure recurrence was 56.6 months, and two-thirds of patients relapsed in the 5 years after surgery. Twenty of the relapse patients only experienced a single seizure, and 41% of the patients who reported more than one seizure had a frequency of less than one per month.
The type of resection had no discernible impact on outcomes, although anterior temporal lobe resection did trend toward being associated with recurrence (odds ratio, 2.7; 95% confidence interval, 0.93-8.89; P = .06). Incomplete resection was significantly associated with late relapse but did not seem to affect timing: the mean duration of seizure freedom was 56.5 months with complete resection and 58.5 months with incomplete resection (P = .62). Additional preoperative PET scans were performed on 45% of patients in the relapse group, compared with 29% in the control group.
After multivariate analysis, predictors for late relapse included incomplete resection (OR, 3.81; 95% CI, 1.79-8.53; P < .001); the existence of additional, potentially epileptogenic lesions in the contralateral hemisphere on presurgical MRI (OR, 3.36; 95% CI, 1.18-10.62; P = .03); epilepsy onset during the first year of life (OR, 4.24; 95% CI, 1.4-15.89; P = .02); and preoperative PET scans being performed (OR, 2.47; 95% CI, 1.25-4.97; P = .01). Though use of preoperative and postoperative antiepileptic drugs (AEDs) was higher in the relapse group, along with complete withdrawal being more common in the control group (68%, compared with 51%), neither was deemed significant in multivariate analysis.
What to do about seizure relapse risk factors
“This is one of the best analyses of the factors that contribute to late seizure relapse,” Gregory K. Bergey, MD, director of the Johns Hopkins Epilepsy Center in Baltimore, said in an interview. “Am I surprised by their results? Not necessarily.”
What did jump out, he said, was AED use not being a predictor of recurrence, as well as all the patients with late relapse having lesional epilepsy. “As they point out, you can have relapse with nonlesional epilepsy, but very often it happens in the first year or 2. If someone is 2 years out and doesn’t have a lesion, they’re probably more likely to remain seizure free.”
Despite the researchers’ comprehensive review of risk factors, the question remains: What to do with this information?
“They’ve done a very good job of identifying that 7.7% of 1,200 who are at risk of a late relapse,” he said. “Now, take those patients with high-risk factors and launch a trial where you keep medicines the same or do something that would alter that outcome.”
“The problem is,” he added, “that’s a 10-year study. It’s easy for me to sit here and call for one of those. But still, as valuable as this was, it’s a retrospective study. Now you have to say, what are the implications of this? What can we do in the prospective fashion?”
The authors acknowledged their study’s other limitations, including a lack of information on the reasons for an incomplete resection, a notable decrease in follow-up visits more than 5 years after surgery, and potential selection bias. They added, however, that “matching by age at surgery, gender, and time to relapse/last follow‐up” should have helped reduce any significant bias.
No potential conflicts of interest were disclosed.
according to a new study on the factors most associated with seizure recurrence in drug-resistant epilepsy.
“As our study analyzed late seizure relapse, our results are not applicable for short‐term seizure control. Vice versa, results for short‐term outcomes should not be transferred to long‐term outcomes,” Stephan Petrik of the Epilepsy Center at the University of Freiburg (Germany) and colleagues wrote. The study was published in the May 2021 issue of Epilepsia.
To assess the variables that increase risk of late seizure recurrence following surgery, the researchers retrospectively studied the medical records of patients who underwent resective epilepsy surgery at the University Hospital Freiburg (Germany) between 1999 and 2015. Of the 1,278 initial patients, a group of 99 participants (7.7%) with seizure relapses after at least 2 years of complete seizure freedom were matched with controls experiencing long-term seizure freedom. The two groups had similar mean durations of epilepsy from onset to surgery: 13.9 years in the relapse group and 13.0 years in the control group.
The mean follow-up was 9.7 years (standard deviation, 4.0; range, 2.9-18.5) in the relapse group and 8.2 years (SD, 3.5; range, 2.2-18.3) in the control group. The mean time to late seizure recurrence was 56.6 months, and two-thirds of patients relapsed in the 5 years after surgery. Twenty of the relapse patients only experienced a single seizure, and 41% of the patients who reported more than one seizure had a frequency of less than one per month.
The type of resection had no discernible impact on outcomes, although anterior temporal lobe resection did trend toward being associated with recurrence (odds ratio, 2.7; 95% confidence interval, 0.93-8.89; P = .06). Incomplete resection was significantly associated with late relapse but did not seem to affect timing: the mean duration of seizure freedom was 56.5 months with complete resection and 58.5 months with incomplete resection (P = .62). Additional preoperative PET scans were performed on 45% of patients in the relapse group, compared with 29% in the control group.
After multivariate analysis, predictors for late relapse included incomplete resection (OR, 3.81; 95% CI, 1.79-8.53; P < .001); the existence of additional, potentially epileptogenic lesions in the contralateral hemisphere on presurgical MRI (OR, 3.36; 95% CI, 1.18-10.62; P = .03); epilepsy onset during the first year of life (OR, 4.24; 95% CI, 1.4-15.89; P = .02); and preoperative PET scans being performed (OR, 2.47; 95% CI, 1.25-4.97; P = .01). Though use of preoperative and postoperative antiepileptic drugs (AEDs) was higher in the relapse group, along with complete withdrawal being more common in the control group (68%, compared with 51%), neither was deemed significant in multivariate analysis.
What to do about seizure relapse risk factors
“This is one of the best analyses of the factors that contribute to late seizure relapse,” Gregory K. Bergey, MD, director of the Johns Hopkins Epilepsy Center in Baltimore, said in an interview. “Am I surprised by their results? Not necessarily.”
What did jump out, he said, was AED use not being a predictor of recurrence, as well as all the patients with late relapse having lesional epilepsy. “As they point out, you can have relapse with nonlesional epilepsy, but very often it happens in the first year or 2. If someone is 2 years out and doesn’t have a lesion, they’re probably more likely to remain seizure free.”
Despite the researchers’ comprehensive review of risk factors, the question remains: What to do with this information?
“They’ve done a very good job of identifying that 7.7% of 1,200 who are at risk of a late relapse,” he said. “Now, take those patients with high-risk factors and launch a trial where you keep medicines the same or do something that would alter that outcome.”
“The problem is,” he added, “that’s a 10-year study. It’s easy for me to sit here and call for one of those. But still, as valuable as this was, it’s a retrospective study. Now you have to say, what are the implications of this? What can we do in the prospective fashion?”
The authors acknowledged their study’s other limitations, including a lack of information on the reasons for an incomplete resection, a notable decrease in follow-up visits more than 5 years after surgery, and potential selection bias. They added, however, that “matching by age at surgery, gender, and time to relapse/last follow‐up” should have helped reduce any significant bias.
No potential conflicts of interest were disclosed.
FROM EPILEPSIA
Female rheumatologists see fewer patients, earn less than males
A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.
“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.
To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.
Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.
Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.
An opportunity for female rheumatologists to reshape the specialty
Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”
“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”
Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.
“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”
Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”
The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”
The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.
“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.
To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.
Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.
Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.
An opportunity for female rheumatologists to reshape the specialty
Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”
“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”
Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.
“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”
Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”
The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”
The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.
“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.
To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.
Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.
Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.
An opportunity for female rheumatologists to reshape the specialty
Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”
“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”
Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.
“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”
Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”
The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”
The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
FROM THE JOURNAL OF RHEUMATOLOGY
Rheumatology clinics find success with smoking cessation referral program
A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.
“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.
To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.
Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.
Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).
Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.
Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.
Rheumatologists can make headway on patients quitting smoking
“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”
In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”
The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”
The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.
A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.
“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.
To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.
Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.
Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).
Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.
Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.
Rheumatologists can make headway on patients quitting smoking
“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”
In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”
The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”
The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.
A new protocol designed to help patients in rheumatology clinics quit smoking proved both efficient and effective in referring willing participants to free tobacco quit lines.
“Rheumatology visits provide a unique opportunity to address smoking as a chronic modifiable risk factor in populations at high risk for cardiovascular disease, pulmonary disease, and rheumatic disease progression,” wrote Christie M. Bartels, MD, chief of the division of rheumatology at the University of Wisconsin, Madison, and colleagues. The study was published in Arthritis Care & Research.
To assess the effectiveness of implementing a smoking cessation protocol for patients with rheumatic diseases, the researchers launched a quasi-experimental cohort study in which their Quit Connect protocol was tested at three rheumatology clinics. Adapting the Ask, Advise, Connect primary care protocol to a new setting, nurses and medical assistants were trained to use electronic health record (EHR) prompts that would check if patients who smoked were ready to quit within 30 days, advise them to do so, and then use electronic referrals to connect them to state-run tobacco quit lines. An extended baseline period – October 2012 to March 2016 – was compared to a 6-month intervention period from April to October 2016.
Across 54,090 pre- and postimplementation rheumatology clinic visits, 4,601 were with current smokers. Demographics were similar across both periods: The mean age of the patients was 51 years, about two-thirds were female, and 85% were White.
Clinicians’ assessment of tobacco use before and after implementation of the program stayed steady at 96% of patient visits, but the percentage of tobacco users’ visits that included checking for readiness to quit within the next 30 days rose from 3% (135 of 4,078) to 80% (421 of 523).
Before the implementation of the program, 0.6% of eligible visits with current smokers included a quit-line referral offer. After implementation, 93 (18%) of the 523 smokers who visited – 122 of whom said they were ready to quit – were offered referrals, a 26-fold increase. Of the 93 offered referrals, 66 (71%) accepted and 16 set a quit date or reported having quit; 11 accepted counseling services and nicotine replacement.
Although clinic staff reported encountering several obstacles, such as the need to craft nonthreatening language for challenging patients, they also contributed their own talking points that were included in the EHR tools and desktop brochures. On average, the protocol took less than 90 seconds to perform.
Rheumatologists can make headway on patients quitting smoking
“While smoking cessation programs require time and resources to implement, this study suggests a role for evidence-based protocols within rheumatology centers,” Medha Barbhaiya, MD, a rheumatologist at the Hospital for Special Surgery in New York, said in an interview. “Given that current smokers are at an increased risk of developing more severe rheumatic disease and cardiovascular disease, and patients often visit their rheumatologist multiple times yearly, rheumatologists may be well-positioned to address smoking cessation with patients.”
In regard to next steps, she noted that “while future large studies in diverse cohorts are needed to confirm these findings, implementing a formal smoking cessation protocol within rheumatology centers may provide a unique opportunity for rheumatologists to directly help patients modify their disease risk, leading to improved health outcomes.”
The authors acknowledged their study’s limitations, including the fact that it was a prepost design and not a randomized trial. They also recognized that many tobacco users require 8-10 attempts before permanently quitting, likely lessening the lasting impact of the short-term study. They did cite expert analysis, however, that says “connecting patients to evidence-based resources makes them more likely to permanently quit.”
The study was supported in part by Pfizer’s office of Independent Grants for Learning and Change and by a grant collaboration from the University of Wisconsin Clinical and Translational Science Award and the University of Wisconsin School of Medicine and Public Health’s Wisconsin Partnership Program, through the NIH National Center for Advancing Translational Sciences.
FROM ARTHRITIS CARE & RESEARCH
Researchers stress importance of second COVID-19 vaccine dose for infliximab users
Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).
“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.
Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.
A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.
In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.
After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.
Evidence has ‘unclear clinical significance’
“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.
“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
Focus on the second dose of a two-dose regimen
“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”
He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.
“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
Debating the cause of weakened immune responses
“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.
“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?
“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”
That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”
The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.
Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).
“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.
Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.
A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.
In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.
After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.
Evidence has ‘unclear clinical significance’
“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.
“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
Focus on the second dose of a two-dose regimen
“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”
He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.
“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
Debating the cause of weakened immune responses
“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.
“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?
“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”
That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”
The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.
Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).
“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.
Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.
A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.
In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.
After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.
Evidence has ‘unclear clinical significance’
“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.
“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
Focus on the second dose of a two-dose regimen
“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”
He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.
“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
Debating the cause of weakened immune responses
“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.
“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?
“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”
That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”
The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.
FROM MEDRXIV