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In Crohn’s Disease, Early Anti-TNF Levels May be Crucial
“The relationship between drug concentrations, immunogenicity and clinical response is likely to be multidirectional; as an observational study, we cannot definitively show the low drug levels are causative. However, our data are consistent with those from elsewhere and confirm the importance of achieving good drug levels to maximize the chances of success with anti-TNF therapy,” said Nicholas Kennedy, MBBS, PhD, a consultant gastroenterologist at Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom, and coauthor of the study published in The Lancet Gastroenterology & Hepatology .
“We also showed that adequate dosing of thiopurines was needed to prevent immunogenicity, along the lines typically used to treat Crohn’s disease rather than the lower doses sometimes proposed,” he added.
The findings come from the Personalized Anti-TNF Therapy in Crohn’s Disease (PANTS) study conducted in the UK, which included 955 patients treated with infliximab and 655 treated with adalimumab between March 2014 and September 2017. The participants were 6 years or older, the median age was 32.5 years, and 51% were female.
The latest findings come from a 2-year extension of the original 1-year PANTS study, published in 2019, which found that low drug concentrations predicted anti-TNF treatment failure — a result likely attributable in part to immunogenicity, since low-drug concentrations predicted the presence of anti-drug antibodies, and anti-drug antibodies in turn predicted low drug concentrations, according to Miguel Regueiro, MD, AGAF, chief of the Digestive Diseases Institute and a professor of medicine at the Cleveland Clinic, Ohio.
“This is one of the more important studies looking at the longitudinal care of patients with Crohn’s disease on infliximab and adalimumab,” said Dr. Regueiro, who was not involved with the study.
The extension study found that anti-drug antibodies and undetectable drug levels were associated with both treatment without an accompanying immunomodulator and carriage of the HLA-DQA1*05 genetic risk factor, though the latter was true only for treatment with infliximab.
Dr. Regueiro noted that the study demonstrates that “getting it right in induction is probably the most important part” of treating Crohn’s disease.
“Getting patients in remission early has probably a long-term prediction [of treatment success]. I do think that is practice changing. My practice has changed over the years, largely based on the initial PANTS study. I am measuring infliximab and adalimumab levels after induction, and I am using that number to decide if I dose intensify the drug, or if I’ve hit that sweet spot,” said Dr. Regueiro.
The study highlights a debate among clinicians, about whether higher drug levels are associated with remission because of the effects of higher doses, or because patients who respond have reduced leakiness in the gut, leading to greater retention of protein therapeutics.
“What the study clearly says is that the drug [level] after induction is important. It implies that there are higher remission rates early. The only thing that it didn’t really tell you is the total inflammatory burden in the body, and [if] lower inflammation equals higher drug level,” said Dr. Regueiro. He did note that the study found that obesity was a negative predictor of long-term remission, which could be attributable to the pro-inflammatory nature of adipose tissue, but he emphasized that the new study doesn’t prove causation.
The study also emphasizes the importance of the HLA-DQA1*05 genetic risk factor.
“I think it confirms that if you’re a carrier of that HLA-DQA1*05, especially with infliximab, if you’re not on an immunomodulator like a thiopurine, you have a very high likelihood of having very high antibodies against infliximab,” Dr. Regueiro said. “The long-term rates bear that out, meaning if you have one of those carriers and you’re not on a thiopurine, the likelihood of having 3-year success on infliximab — to a lesser degree, adalimumab — is very, very low.”
After exclusion of patients who had no initial response, among infliximab patients, the loss of response was 34.4% at 1 year (95% CI, 30.4-38.2%), 54.5% at 2 years (95% CI, 49.4-59%), and 60% at 3 years (95% CI, 54.1-65.2%). For adalimumab, the loss of response rates were 32.1% (95% CI, 26.7-37.1%), 47.2% (95% CI, 40.2-53.4%), and 68.4% (95% CI, 50.9-79.7%), respectively.
Drug concentrations were measured at week 14, and concentration ranges of 6.1-10 mg/L for infliximab and 10.1-12 mg/L for adalimumab were associated with remission at year 2 (infliximab odds ratio [OR], 2.2; 95% CI, 1.38-3.56. Adalimumab OR, 3.65; 95% CI, 1.83-8.67) and year 3 (infliximab OR, 1.89; 95% CI, 1.16-3.11; adalimumab OR, 6.15; 95% CI, 2.5-23.19). A multivariate analysis found that each ten-fold increase in drug concentration at week 14 predicted lower odds of loss of response at year 2 or 3, both for infliximab (hazard ratio [HR], 0.45; 95% CI, 0.3-0.67) and adalimumab (HR, 0.39; 95% CI, 0.22-0.7).
Among patients taking infliximab, loss of response at year 2 or 3 was associated with female sex (HR, 1.47; 95% CI, 1.11-1.95) and obesity (HR, 1.62; 95% CI, 1.08-2.42). After the researchers controlled for week 14 drug and antibody concentrations, as well as interaction between baseline immunomodulator and HLA-DQA1*05 risk variant, low thiopurine dose was associated with a higher risk of loss of response.
In the adalimumab group, there was an association between presence of the HLA-DQA1*05 risk variant and loss of response (HR, 1.95; 95% CI, 1.17-3.25).
Use of the anti-TNF drug without an immunomodulator was associated with development of anti-drug antibodies for infliximab (HR, 0.4; 95% CI, 0.31-0.52) and adalimumab (HR, 0.42; 95% CI, 0.24-0.75). Development of anti-drug antibodies was also associated with the presence of HLA-DQA1*05 for infliximab (HR, 1.46; 95% CI, 1.13-1.88), but not adalimumab (HR, 1.6; 95% CI, 0.92-2.77). Use of an immunomodulator the day before or day of treatment with infliximab was associated with a delay in development of anti-drug antibodies and undetectable drug concentrations compared to only infliximab (HR, 2.87; 95% CI, 2.2-3.74) and to use of the immunomodulator following infliximab treatment (HR, 1.7; 95% CI, 1.11-2.59).
“We suggest aiming to start thiopurines alongside infliximab; our data suggest that later introduction is less effective,” said Dr. Kennedy, who is currently chair of the British Society of Gastroenterology IBD Clinical Research Group.
Dr. Kennedy reported institutional grants or contracts, personal consulting fees, and personal payments or honoraria from a variety of pharmaceutical companies. See the original article for a complete list.
Dr. Regueiro reported that he has been on advisory boards and consulted for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, and Roche.
A version of this article appeared on Medscape.com.
“The relationship between drug concentrations, immunogenicity and clinical response is likely to be multidirectional; as an observational study, we cannot definitively show the low drug levels are causative. However, our data are consistent with those from elsewhere and confirm the importance of achieving good drug levels to maximize the chances of success with anti-TNF therapy,” said Nicholas Kennedy, MBBS, PhD, a consultant gastroenterologist at Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom, and coauthor of the study published in The Lancet Gastroenterology & Hepatology .
“We also showed that adequate dosing of thiopurines was needed to prevent immunogenicity, along the lines typically used to treat Crohn’s disease rather than the lower doses sometimes proposed,” he added.
The findings come from the Personalized Anti-TNF Therapy in Crohn’s Disease (PANTS) study conducted in the UK, which included 955 patients treated with infliximab and 655 treated with adalimumab between March 2014 and September 2017. The participants were 6 years or older, the median age was 32.5 years, and 51% were female.
The latest findings come from a 2-year extension of the original 1-year PANTS study, published in 2019, which found that low drug concentrations predicted anti-TNF treatment failure — a result likely attributable in part to immunogenicity, since low-drug concentrations predicted the presence of anti-drug antibodies, and anti-drug antibodies in turn predicted low drug concentrations, according to Miguel Regueiro, MD, AGAF, chief of the Digestive Diseases Institute and a professor of medicine at the Cleveland Clinic, Ohio.
“This is one of the more important studies looking at the longitudinal care of patients with Crohn’s disease on infliximab and adalimumab,” said Dr. Regueiro, who was not involved with the study.
The extension study found that anti-drug antibodies and undetectable drug levels were associated with both treatment without an accompanying immunomodulator and carriage of the HLA-DQA1*05 genetic risk factor, though the latter was true only for treatment with infliximab.
Dr. Regueiro noted that the study demonstrates that “getting it right in induction is probably the most important part” of treating Crohn’s disease.
“Getting patients in remission early has probably a long-term prediction [of treatment success]. I do think that is practice changing. My practice has changed over the years, largely based on the initial PANTS study. I am measuring infliximab and adalimumab levels after induction, and I am using that number to decide if I dose intensify the drug, or if I’ve hit that sweet spot,” said Dr. Regueiro.
The study highlights a debate among clinicians, about whether higher drug levels are associated with remission because of the effects of higher doses, or because patients who respond have reduced leakiness in the gut, leading to greater retention of protein therapeutics.
“What the study clearly says is that the drug [level] after induction is important. It implies that there are higher remission rates early. The only thing that it didn’t really tell you is the total inflammatory burden in the body, and [if] lower inflammation equals higher drug level,” said Dr. Regueiro. He did note that the study found that obesity was a negative predictor of long-term remission, which could be attributable to the pro-inflammatory nature of adipose tissue, but he emphasized that the new study doesn’t prove causation.
The study also emphasizes the importance of the HLA-DQA1*05 genetic risk factor.
“I think it confirms that if you’re a carrier of that HLA-DQA1*05, especially with infliximab, if you’re not on an immunomodulator like a thiopurine, you have a very high likelihood of having very high antibodies against infliximab,” Dr. Regueiro said. “The long-term rates bear that out, meaning if you have one of those carriers and you’re not on a thiopurine, the likelihood of having 3-year success on infliximab — to a lesser degree, adalimumab — is very, very low.”
After exclusion of patients who had no initial response, among infliximab patients, the loss of response was 34.4% at 1 year (95% CI, 30.4-38.2%), 54.5% at 2 years (95% CI, 49.4-59%), and 60% at 3 years (95% CI, 54.1-65.2%). For adalimumab, the loss of response rates were 32.1% (95% CI, 26.7-37.1%), 47.2% (95% CI, 40.2-53.4%), and 68.4% (95% CI, 50.9-79.7%), respectively.
Drug concentrations were measured at week 14, and concentration ranges of 6.1-10 mg/L for infliximab and 10.1-12 mg/L for adalimumab were associated with remission at year 2 (infliximab odds ratio [OR], 2.2; 95% CI, 1.38-3.56. Adalimumab OR, 3.65; 95% CI, 1.83-8.67) and year 3 (infliximab OR, 1.89; 95% CI, 1.16-3.11; adalimumab OR, 6.15; 95% CI, 2.5-23.19). A multivariate analysis found that each ten-fold increase in drug concentration at week 14 predicted lower odds of loss of response at year 2 or 3, both for infliximab (hazard ratio [HR], 0.45; 95% CI, 0.3-0.67) and adalimumab (HR, 0.39; 95% CI, 0.22-0.7).
Among patients taking infliximab, loss of response at year 2 or 3 was associated with female sex (HR, 1.47; 95% CI, 1.11-1.95) and obesity (HR, 1.62; 95% CI, 1.08-2.42). After the researchers controlled for week 14 drug and antibody concentrations, as well as interaction between baseline immunomodulator and HLA-DQA1*05 risk variant, low thiopurine dose was associated with a higher risk of loss of response.
In the adalimumab group, there was an association between presence of the HLA-DQA1*05 risk variant and loss of response (HR, 1.95; 95% CI, 1.17-3.25).
Use of the anti-TNF drug without an immunomodulator was associated with development of anti-drug antibodies for infliximab (HR, 0.4; 95% CI, 0.31-0.52) and adalimumab (HR, 0.42; 95% CI, 0.24-0.75). Development of anti-drug antibodies was also associated with the presence of HLA-DQA1*05 for infliximab (HR, 1.46; 95% CI, 1.13-1.88), but not adalimumab (HR, 1.6; 95% CI, 0.92-2.77). Use of an immunomodulator the day before or day of treatment with infliximab was associated with a delay in development of anti-drug antibodies and undetectable drug concentrations compared to only infliximab (HR, 2.87; 95% CI, 2.2-3.74) and to use of the immunomodulator following infliximab treatment (HR, 1.7; 95% CI, 1.11-2.59).
“We suggest aiming to start thiopurines alongside infliximab; our data suggest that later introduction is less effective,” said Dr. Kennedy, who is currently chair of the British Society of Gastroenterology IBD Clinical Research Group.
Dr. Kennedy reported institutional grants or contracts, personal consulting fees, and personal payments or honoraria from a variety of pharmaceutical companies. See the original article for a complete list.
Dr. Regueiro reported that he has been on advisory boards and consulted for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, and Roche.
A version of this article appeared on Medscape.com.
“The relationship between drug concentrations, immunogenicity and clinical response is likely to be multidirectional; as an observational study, we cannot definitively show the low drug levels are causative. However, our data are consistent with those from elsewhere and confirm the importance of achieving good drug levels to maximize the chances of success with anti-TNF therapy,” said Nicholas Kennedy, MBBS, PhD, a consultant gastroenterologist at Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom, and coauthor of the study published in The Lancet Gastroenterology & Hepatology .
“We also showed that adequate dosing of thiopurines was needed to prevent immunogenicity, along the lines typically used to treat Crohn’s disease rather than the lower doses sometimes proposed,” he added.
The findings come from the Personalized Anti-TNF Therapy in Crohn’s Disease (PANTS) study conducted in the UK, which included 955 patients treated with infliximab and 655 treated with adalimumab between March 2014 and September 2017. The participants were 6 years or older, the median age was 32.5 years, and 51% were female.
The latest findings come from a 2-year extension of the original 1-year PANTS study, published in 2019, which found that low drug concentrations predicted anti-TNF treatment failure — a result likely attributable in part to immunogenicity, since low-drug concentrations predicted the presence of anti-drug antibodies, and anti-drug antibodies in turn predicted low drug concentrations, according to Miguel Regueiro, MD, AGAF, chief of the Digestive Diseases Institute and a professor of medicine at the Cleveland Clinic, Ohio.
“This is one of the more important studies looking at the longitudinal care of patients with Crohn’s disease on infliximab and adalimumab,” said Dr. Regueiro, who was not involved with the study.
The extension study found that anti-drug antibodies and undetectable drug levels were associated with both treatment without an accompanying immunomodulator and carriage of the HLA-DQA1*05 genetic risk factor, though the latter was true only for treatment with infliximab.
Dr. Regueiro noted that the study demonstrates that “getting it right in induction is probably the most important part” of treating Crohn’s disease.
“Getting patients in remission early has probably a long-term prediction [of treatment success]. I do think that is practice changing. My practice has changed over the years, largely based on the initial PANTS study. I am measuring infliximab and adalimumab levels after induction, and I am using that number to decide if I dose intensify the drug, or if I’ve hit that sweet spot,” said Dr. Regueiro.
The study highlights a debate among clinicians, about whether higher drug levels are associated with remission because of the effects of higher doses, or because patients who respond have reduced leakiness in the gut, leading to greater retention of protein therapeutics.
“What the study clearly says is that the drug [level] after induction is important. It implies that there are higher remission rates early. The only thing that it didn’t really tell you is the total inflammatory burden in the body, and [if] lower inflammation equals higher drug level,” said Dr. Regueiro. He did note that the study found that obesity was a negative predictor of long-term remission, which could be attributable to the pro-inflammatory nature of adipose tissue, but he emphasized that the new study doesn’t prove causation.
The study also emphasizes the importance of the HLA-DQA1*05 genetic risk factor.
“I think it confirms that if you’re a carrier of that HLA-DQA1*05, especially with infliximab, if you’re not on an immunomodulator like a thiopurine, you have a very high likelihood of having very high antibodies against infliximab,” Dr. Regueiro said. “The long-term rates bear that out, meaning if you have one of those carriers and you’re not on a thiopurine, the likelihood of having 3-year success on infliximab — to a lesser degree, adalimumab — is very, very low.”
After exclusion of patients who had no initial response, among infliximab patients, the loss of response was 34.4% at 1 year (95% CI, 30.4-38.2%), 54.5% at 2 years (95% CI, 49.4-59%), and 60% at 3 years (95% CI, 54.1-65.2%). For adalimumab, the loss of response rates were 32.1% (95% CI, 26.7-37.1%), 47.2% (95% CI, 40.2-53.4%), and 68.4% (95% CI, 50.9-79.7%), respectively.
Drug concentrations were measured at week 14, and concentration ranges of 6.1-10 mg/L for infliximab and 10.1-12 mg/L for adalimumab were associated with remission at year 2 (infliximab odds ratio [OR], 2.2; 95% CI, 1.38-3.56. Adalimumab OR, 3.65; 95% CI, 1.83-8.67) and year 3 (infliximab OR, 1.89; 95% CI, 1.16-3.11; adalimumab OR, 6.15; 95% CI, 2.5-23.19). A multivariate analysis found that each ten-fold increase in drug concentration at week 14 predicted lower odds of loss of response at year 2 or 3, both for infliximab (hazard ratio [HR], 0.45; 95% CI, 0.3-0.67) and adalimumab (HR, 0.39; 95% CI, 0.22-0.7).
Among patients taking infliximab, loss of response at year 2 or 3 was associated with female sex (HR, 1.47; 95% CI, 1.11-1.95) and obesity (HR, 1.62; 95% CI, 1.08-2.42). After the researchers controlled for week 14 drug and antibody concentrations, as well as interaction between baseline immunomodulator and HLA-DQA1*05 risk variant, low thiopurine dose was associated with a higher risk of loss of response.
In the adalimumab group, there was an association between presence of the HLA-DQA1*05 risk variant and loss of response (HR, 1.95; 95% CI, 1.17-3.25).
Use of the anti-TNF drug without an immunomodulator was associated with development of anti-drug antibodies for infliximab (HR, 0.4; 95% CI, 0.31-0.52) and adalimumab (HR, 0.42; 95% CI, 0.24-0.75). Development of anti-drug antibodies was also associated with the presence of HLA-DQA1*05 for infliximab (HR, 1.46; 95% CI, 1.13-1.88), but not adalimumab (HR, 1.6; 95% CI, 0.92-2.77). Use of an immunomodulator the day before or day of treatment with infliximab was associated with a delay in development of anti-drug antibodies and undetectable drug concentrations compared to only infliximab (HR, 2.87; 95% CI, 2.2-3.74) and to use of the immunomodulator following infliximab treatment (HR, 1.7; 95% CI, 1.11-2.59).
“We suggest aiming to start thiopurines alongside infliximab; our data suggest that later introduction is less effective,” said Dr. Kennedy, who is currently chair of the British Society of Gastroenterology IBD Clinical Research Group.
Dr. Kennedy reported institutional grants or contracts, personal consulting fees, and personal payments or honoraria from a variety of pharmaceutical companies. See the original article for a complete list.
Dr. Regueiro reported that he has been on advisory boards and consulted for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, and Roche.
A version of this article appeared on Medscape.com.
Nasal Staph Aureus Carriage Linked to Surgical Infections
published in the August issue of Open Forum Infectious Diseases.
“This was a pan-European study with many hospitals, many different clinical settings, and as far as I’m aware, it hasn’t been done before. [The new study] covers a lot of European countries and a lot of surgical specialties,” said lead author Jan Kluytmans, MD. The study also captures the current state of preventive strategies in surgery, such as changes in air flow, dress, and skin preparation, he added.
The study included 5004 patients from 33 hospitals in ten European countries, of whom 67.3% were found to be SA carriers. The median age was 65 years, and 49.8% of patients were male. Open cardiac, and knee and hip prosthesis surgeries made up the largest fraction, but there were 12 types of surgery included in the study.
There were 100 SA surgical site or blood infections. The researchers found an association between surgical site or blood infection and SA carriage at any site (adjusted hazard ratio [aHR], 4.6; 95% CI, 2.1-10.0) and nasal SA carriage (aHR, 4.2; 95% CI, 2.0-8.6). Extranasal SA carriage was not associated with an increased infection risk.
Each 1-unit increase in nasal bacteria was associated with an increase in infection risk (aHR, 1.23; 95% CI, 1.05-1.43).
A strength of the study is that it is the largest prospective study yet conducted on SA carriage in surgical patients, but the researchers were unable to do a subgroup of methicillin-resistant SA (MRSA) due to small numbers of infections.
The study confirms the value of the decolonization strategy, which the World Health Organization has endorsed with the highest level of scientific evidence that is available in preventive strategies in surgery. WHO strongly recommends decolonization for cardiothoracic and orthopedic surgery using intranasal applications of mupirocin 2% ointment with or without a combination of chlorhexidine gluconate body wash. It has a conditional recommendation for a similar procedure before other types of surgery.
However, “It is not widely practiced, and although that was not a surprise to me, I think it’s really disappointing to see that proven effective strategies are not being practiced,” said Dr. Kluytmans, professor of medical microbiology at University Medical Center Utrecht, Utrecht University, the Netherlands. “If I would come into surgery being a carrier, and not be decolonized, I would really be quite angry because it puts you at risk, which is preventable. I think that’s something we owe to our patients,” he said.
He said that some may have concerns about the potential for decolonization to contribute to antibiotic resistance, but the short-term prophylaxis — typically a few days — should not foster resistance, according to Dr. Kluytmans. “If you use it short term, just before surgery, it has been shown in many studies that resistance isn’t a big problem and it can be monitored.”
The link specifically to SA nasal carriage is a mystery, according to Dr. Kluytmans. “It puzzles me still how it gets from the nares to the wound during surgery. So that’s my million-dollar question that I would like to resolve. We would like to study it, but we haven’t quite a bright idea how to do that,” he said.
The results are compelling, according to Heather Evans, MD, who was asked for comment. “On the face of it, this looks like a no-brainer. We should be decolonizing all patients that go to the operating room, and it’s not a terribly unpleasant thing for a patient to undergo to have decolonization done. Particularly for patients who are at higher risk for having a severe complication, like someone that has an operation that’s involving an implant, for example, I think it really makes a lot of sense to do this low-cost intervention for those patients,” said Dr. Evans, professor of medicine at The Medical University of South Carolina as well as the president of the Surgical Infection Society.
She noted that many facilities test for methicillin-resistant SA, but usual not SA more broadly. “This is a very interesting and compelling study that makes us rethink that, and maybe it isn’t even worth testing to see if you have staph aureus, maybe we should just be putting Betadine in everyone’s nostrils when they come to the operating room. It just seems like it would be a pretty low-cost intervention and something that could potentially have a big impact,” said Dr. Evans.
Although she was impressed by the study, Dr. Evans noted that the researchers tested for carriage at sites unrelated to the surgical site. “It really made me wonder if it would have added even more credibility to the study if there had been a sample taken after surgical prep was done to demonstrate that there is actually no staph aureus present on the skin at the time that the wound was made,” she said.
The question ties into the recent “Trojan horse” hypothesis, which suggests that endemic carriage of bacteria is responsible for most surgical site infections, rather than the long-held belief that operating room contamination is to blame. “That would sort of fly with this study, that the patient is walking around with Staph aureus and not necessarily on their skin or at their surgical site, but it’s endemic in their body,” said Dr. Evans.
Dr. Kluytmans and Dr. Evans have no relevant financial disclosures.
published in the August issue of Open Forum Infectious Diseases.
“This was a pan-European study with many hospitals, many different clinical settings, and as far as I’m aware, it hasn’t been done before. [The new study] covers a lot of European countries and a lot of surgical specialties,” said lead author Jan Kluytmans, MD. The study also captures the current state of preventive strategies in surgery, such as changes in air flow, dress, and skin preparation, he added.
The study included 5004 patients from 33 hospitals in ten European countries, of whom 67.3% were found to be SA carriers. The median age was 65 years, and 49.8% of patients were male. Open cardiac, and knee and hip prosthesis surgeries made up the largest fraction, but there were 12 types of surgery included in the study.
There were 100 SA surgical site or blood infections. The researchers found an association between surgical site or blood infection and SA carriage at any site (adjusted hazard ratio [aHR], 4.6; 95% CI, 2.1-10.0) and nasal SA carriage (aHR, 4.2; 95% CI, 2.0-8.6). Extranasal SA carriage was not associated with an increased infection risk.
Each 1-unit increase in nasal bacteria was associated with an increase in infection risk (aHR, 1.23; 95% CI, 1.05-1.43).
A strength of the study is that it is the largest prospective study yet conducted on SA carriage in surgical patients, but the researchers were unable to do a subgroup of methicillin-resistant SA (MRSA) due to small numbers of infections.
The study confirms the value of the decolonization strategy, which the World Health Organization has endorsed with the highest level of scientific evidence that is available in preventive strategies in surgery. WHO strongly recommends decolonization for cardiothoracic and orthopedic surgery using intranasal applications of mupirocin 2% ointment with or without a combination of chlorhexidine gluconate body wash. It has a conditional recommendation for a similar procedure before other types of surgery.
However, “It is not widely practiced, and although that was not a surprise to me, I think it’s really disappointing to see that proven effective strategies are not being practiced,” said Dr. Kluytmans, professor of medical microbiology at University Medical Center Utrecht, Utrecht University, the Netherlands. “If I would come into surgery being a carrier, and not be decolonized, I would really be quite angry because it puts you at risk, which is preventable. I think that’s something we owe to our patients,” he said.
He said that some may have concerns about the potential for decolonization to contribute to antibiotic resistance, but the short-term prophylaxis — typically a few days — should not foster resistance, according to Dr. Kluytmans. “If you use it short term, just before surgery, it has been shown in many studies that resistance isn’t a big problem and it can be monitored.”
The link specifically to SA nasal carriage is a mystery, according to Dr. Kluytmans. “It puzzles me still how it gets from the nares to the wound during surgery. So that’s my million-dollar question that I would like to resolve. We would like to study it, but we haven’t quite a bright idea how to do that,” he said.
The results are compelling, according to Heather Evans, MD, who was asked for comment. “On the face of it, this looks like a no-brainer. We should be decolonizing all patients that go to the operating room, and it’s not a terribly unpleasant thing for a patient to undergo to have decolonization done. Particularly for patients who are at higher risk for having a severe complication, like someone that has an operation that’s involving an implant, for example, I think it really makes a lot of sense to do this low-cost intervention for those patients,” said Dr. Evans, professor of medicine at The Medical University of South Carolina as well as the president of the Surgical Infection Society.
She noted that many facilities test for methicillin-resistant SA, but usual not SA more broadly. “This is a very interesting and compelling study that makes us rethink that, and maybe it isn’t even worth testing to see if you have staph aureus, maybe we should just be putting Betadine in everyone’s nostrils when they come to the operating room. It just seems like it would be a pretty low-cost intervention and something that could potentially have a big impact,” said Dr. Evans.
Although she was impressed by the study, Dr. Evans noted that the researchers tested for carriage at sites unrelated to the surgical site. “It really made me wonder if it would have added even more credibility to the study if there had been a sample taken after surgical prep was done to demonstrate that there is actually no staph aureus present on the skin at the time that the wound was made,” she said.
The question ties into the recent “Trojan horse” hypothesis, which suggests that endemic carriage of bacteria is responsible for most surgical site infections, rather than the long-held belief that operating room contamination is to blame. “That would sort of fly with this study, that the patient is walking around with Staph aureus and not necessarily on their skin or at their surgical site, but it’s endemic in their body,” said Dr. Evans.
Dr. Kluytmans and Dr. Evans have no relevant financial disclosures.
published in the August issue of Open Forum Infectious Diseases.
“This was a pan-European study with many hospitals, many different clinical settings, and as far as I’m aware, it hasn’t been done before. [The new study] covers a lot of European countries and a lot of surgical specialties,” said lead author Jan Kluytmans, MD. The study also captures the current state of preventive strategies in surgery, such as changes in air flow, dress, and skin preparation, he added.
The study included 5004 patients from 33 hospitals in ten European countries, of whom 67.3% were found to be SA carriers. The median age was 65 years, and 49.8% of patients were male. Open cardiac, and knee and hip prosthesis surgeries made up the largest fraction, but there were 12 types of surgery included in the study.
There were 100 SA surgical site or blood infections. The researchers found an association between surgical site or blood infection and SA carriage at any site (adjusted hazard ratio [aHR], 4.6; 95% CI, 2.1-10.0) and nasal SA carriage (aHR, 4.2; 95% CI, 2.0-8.6). Extranasal SA carriage was not associated with an increased infection risk.
Each 1-unit increase in nasal bacteria was associated with an increase in infection risk (aHR, 1.23; 95% CI, 1.05-1.43).
A strength of the study is that it is the largest prospective study yet conducted on SA carriage in surgical patients, but the researchers were unable to do a subgroup of methicillin-resistant SA (MRSA) due to small numbers of infections.
The study confirms the value of the decolonization strategy, which the World Health Organization has endorsed with the highest level of scientific evidence that is available in preventive strategies in surgery. WHO strongly recommends decolonization for cardiothoracic and orthopedic surgery using intranasal applications of mupirocin 2% ointment with or without a combination of chlorhexidine gluconate body wash. It has a conditional recommendation for a similar procedure before other types of surgery.
However, “It is not widely practiced, and although that was not a surprise to me, I think it’s really disappointing to see that proven effective strategies are not being practiced,” said Dr. Kluytmans, professor of medical microbiology at University Medical Center Utrecht, Utrecht University, the Netherlands. “If I would come into surgery being a carrier, and not be decolonized, I would really be quite angry because it puts you at risk, which is preventable. I think that’s something we owe to our patients,” he said.
He said that some may have concerns about the potential for decolonization to contribute to antibiotic resistance, but the short-term prophylaxis — typically a few days — should not foster resistance, according to Dr. Kluytmans. “If you use it short term, just before surgery, it has been shown in many studies that resistance isn’t a big problem and it can be monitored.”
The link specifically to SA nasal carriage is a mystery, according to Dr. Kluytmans. “It puzzles me still how it gets from the nares to the wound during surgery. So that’s my million-dollar question that I would like to resolve. We would like to study it, but we haven’t quite a bright idea how to do that,” he said.
The results are compelling, according to Heather Evans, MD, who was asked for comment. “On the face of it, this looks like a no-brainer. We should be decolonizing all patients that go to the operating room, and it’s not a terribly unpleasant thing for a patient to undergo to have decolonization done. Particularly for patients who are at higher risk for having a severe complication, like someone that has an operation that’s involving an implant, for example, I think it really makes a lot of sense to do this low-cost intervention for those patients,” said Dr. Evans, professor of medicine at The Medical University of South Carolina as well as the president of the Surgical Infection Society.
She noted that many facilities test for methicillin-resistant SA, but usual not SA more broadly. “This is a very interesting and compelling study that makes us rethink that, and maybe it isn’t even worth testing to see if you have staph aureus, maybe we should just be putting Betadine in everyone’s nostrils when they come to the operating room. It just seems like it would be a pretty low-cost intervention and something that could potentially have a big impact,” said Dr. Evans.
Although she was impressed by the study, Dr. Evans noted that the researchers tested for carriage at sites unrelated to the surgical site. “It really made me wonder if it would have added even more credibility to the study if there had been a sample taken after surgical prep was done to demonstrate that there is actually no staph aureus present on the skin at the time that the wound was made,” she said.
The question ties into the recent “Trojan horse” hypothesis, which suggests that endemic carriage of bacteria is responsible for most surgical site infections, rather than the long-held belief that operating room contamination is to blame. “That would sort of fly with this study, that the patient is walking around with Staph aureus and not necessarily on their skin or at their surgical site, but it’s endemic in their body,” said Dr. Evans.
Dr. Kluytmans and Dr. Evans have no relevant financial disclosures.
Study Finds Differences in Side Effect Profiles With Two Oral Psoriasis Therapies
TOPLINE:
, according to a retrospective comparison using US Food and Drug Administration (FDA) data.
METHODOLOGY:
- To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
- The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
- AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.
TAKEAWAY:
- There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
- The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
- The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
- Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.
IN PRACTICE:
The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.
SOURCE:
Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.
LIMITATIONS:
The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.
DISCLOSURES:
The study received no funding, and the authors had no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
TOPLINE:
, according to a retrospective comparison using US Food and Drug Administration (FDA) data.
METHODOLOGY:
- To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
- The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
- AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.
TAKEAWAY:
- There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
- The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
- The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
- Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.
IN PRACTICE:
The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.
SOURCE:
Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.
LIMITATIONS:
The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.
DISCLOSURES:
The study received no funding, and the authors had no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
TOPLINE:
, according to a retrospective comparison using US Food and Drug Administration (FDA) data.
METHODOLOGY:
- To evaluate the adverse events associated with apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, and deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, data were drawn from the FDA’s Adverse Event Reporting System database.
- The Medex_UIMA_1.8.3 system was used to standardize drug names, and MedDRA terminology was used to encode, categorize, and localize signals.
- AE event signals were grouped by skin and subcutaneous tissue disorders, gastrointestinal disorders, infections and infestations, and nervous system disorders.
TAKEAWAY:
- There were 95,734 AE reports for apremilast and 760 AE reports for deucravacitinib, and AEs were found to be significant over time.
- The more common cutaneous AEs were psoriasis recurrence and acne (associated with apremilast) and skin burning and erythema (associated with deucravacitinib).
- The more common gastrointestinal AEs were diarrhea and nausea (apremilast) and mouth ulceration (deucravacitinib).
- Deucravacitinib-related pruritus and rash, as well as apremilast-related tension headache, were more common in women than men; deucravacitinib-related skin burning was more common in men.
IN PRACTICE:
The results “can help the doctors to choose the right treatment options based on the baseline characteristics of different patients,” said Yuanyuan Xu, a graduate student in the Department of Dermatology, Sichuan University, Chengdu, China.
SOURCE:
Mr. Xu presented the study as a poster at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2024 annual meeting.
LIMITATIONS:
The study was retrospective and cannot prove causality, and there were far fewer AE reports related to deucravacitinib, likely because the drug was introduced more recently.
DISCLOSURES:
The study received no funding, and the authors had no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
Risk of MACE Comparable Among Biologic Classes for Psoriasis, PsA
TOPLINE:
a database analysis finds.
METHODOLOGY:
- Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
- The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
- Subset analyses compared MACE in patients with and without existing cardiovascular disease.
TAKEAWAY:
- Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
- There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.
IN PRACTICE:
Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.
SOURCE:
Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
LIMITATIONS:
The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.
DISCLOSURES:
Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.
A version of this article first appeared on Medscape.com.
TOPLINE:
a database analysis finds.
METHODOLOGY:
- Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
- The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
- Subset analyses compared MACE in patients with and without existing cardiovascular disease.
TAKEAWAY:
- Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
- There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.
IN PRACTICE:
Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.
SOURCE:
Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
LIMITATIONS:
The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.
DISCLOSURES:
Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.
A version of this article first appeared on Medscape.com.
TOPLINE:
a database analysis finds.
METHODOLOGY:
- Data from the TriNetX health records database included 32,758 patients treated with TNF inhibitors (TNFi, 62.9%), interleukin-17 inhibitors (IL-17i, 15.4%), IL-23i (10.7%), and IL-12i/IL-23i (10.7%).
- The researchers calculated time-dependent risk for MACE using multinomial Cox proportional hazard ratios. The reference was TNFi exposure.
- Subset analyses compared MACE in patients with and without existing cardiovascular disease.
TAKEAWAY:
- Compared with TNFi use, there was no difference in the incidence of MACE events in the IL-17i, IL-23i, or IL-12i/IL-23i group.
- There were also no significant differences between biologic groups in the incidence of congestive heart failure, myocardial infarction, or cerebral vascular accident/stroke.
IN PRACTICE:
Despite some concern about increased risk for MACE with TNFi use, this study suggests no special risk for patients with psoriasis or PsA associated with TNFi vs other biologics. “Given our results, as it pertains to MACE, prescribers shouldn’t favor any one biologic class over another,” said lead investigator Shikha Singla, MD, medical director of the Psoriatic Arthritis Program at Medical College of Wisconsin in Milwaukee, Wisconsin.
SOURCE:
Bonit Gill, MD, a second-year fellow at Medical College of Wisconsin, presented the study as a poster at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
LIMITATIONS:
The study’s retrospective nature makes it impossible to prove causation and the patients included in the study were from Wisconsin, which may limit generalizability.
DISCLOSURES:
Dr. Gill had no relevant financial disclosures. Other study authors participated in trials or consulted for AbbVie, AstraZeneca, Novartis, Eli Lilly, Janssen, and UCB.
A version of this article first appeared on Medscape.com.
Mysteries Persist About Tissue Resident Memory T Cells in Psoriasis
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
FROM GRAPPA 2024
Debate: Should Dermatologists or Rheumatologists Manage Musculoskeletal Symptoms in Patients With Psoriasis?
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
FROM GRAPPA 2024
Eptinezumab Inhibitor Fails Cluster Headache Test
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
SAN DIEGO — However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.
Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society
Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
Are We Looking at the Wrong Endpoint?
Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.
He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.
Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.
The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.
The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
Thoughts on Redesigning Cluster Headache Clinical Trials
During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.
Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.
Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.
FROM AHS 2024
Migraine Linked to Cardiovascular Risk in Veterans Study
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
FROM AHS 2024
New Survey Explores New Daily Persistent Headache
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
SAN DIEGO —
“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.
There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.
The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.
Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
Additional Information on a Rare, Hard-to-Treat Condition
Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.
He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.
The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
‘A Good Data Set’
The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.
The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
Insights Into Treatment Efficacy
Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’
“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.
There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.
Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.
FROM AHS 2024
Lidocaine Effective Against Pediatric Migraine
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
SAN DIEGO — The treatment has long been used in adults, and frequently in children on the strength of observational evidence.
Prior Research
Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.
Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.
“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.
The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”
She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
A Randomized, Controlled Trial
In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.
There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.
After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.
Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
Important Research in an Understudied Population
Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.
Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.
FROM AHS 2024