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Analysis boosts fluvoxamine for COVID, but what’s the evidence?
a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.
The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.
“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”
According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.
A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”
For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.
Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.
All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.
“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I2, 0.2%).”
Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.
Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”
Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”
The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”
In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”
He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”
Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”
He also noted that the three studies “are very different in design and endpoints.”
Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”
No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.
The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.
“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”
According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.
A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”
For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.
Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.
All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.
“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I2, 0.2%).”
Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.
Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”
Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”
The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”
In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”
He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”
Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”
He also noted that the three studies “are very different in design and endpoints.”
Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”
No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.
The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.
“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”
According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.
A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”
For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.
Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.
All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.
“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I2, 0.2%).”
Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.
Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”
Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”
The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”
In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”
He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”
Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”
He also noted that the three studies “are very different in design and endpoints.”
Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”
No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
First-line CAR T-cell therapy could help cure some lymphomas
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
FROM NATURE MEDICINE
COVID-19–alopecia areata link? Review doesn’t find much evidence
A new
If there is a connection, it’s likely not a strong one, said study author Rachel E. Christensen, a graduate student at Rutgers Robert Wood Johnson Medical School, in an interview. “Based on the reported number of cases following COVID-19, alopecia areata appears to be low on the list of common skin manifestations of COVID-19,” she said. Of 402 articles screened from three databases in the review, only 11 were identified as related to alopecia areata (AA) and COVID-19, and only 9 of those met the study inclusion criteria. “This number alone highlights the very low number of published articles investigating this connection.”
The review was published in JAAD International.
While COVID-19 has been linked to a variety of skin conditions, a 2021 South Korean study of 7,958 cases and 218,779 controls found no connection between infection and AA even after covariates such as age, gender, and income level were taken into account. In a letter to the editor published in 2020, dermatologists in Turkey reported that the percentage of patients with AA at the dermatology outpatient clinic jumped from 0.97% in May 2019 to 1.48% in May 2020. The number of patients in each group wasn’t reported.
Systematic review
The investigators launched the systematic review to gain a wider perspective, although there are still limitations. On the one hand, Ms. Christensen said, “we do know that COVID-19, like other viruses, has been linked to various dermatological disorders.”
However, “it is difficult to tease apart whether any worsening of alopecia areata we see following COVID-19 is due to the virus itself or the increased psychological burden related to the infection or to the pandemic in general,” she said. Indeed, the authors of the report in Turkey attributed the rise in cases to stress.
For the review, the researchers analyzed studies from Italy (four), Turkey (two), Brazil (one), the United States (one), and Poland (one).
Six of the studies reported cases of new-onset AA following COVID-19 infection (seven cases; average age, 37 years; females, three). Another study was a retrospective review of 32 patients with preexisting AA who developed COVID-19; none experienced significant worsening of AA within 6 months.
The review also included a study based on a survey of 389 patients with AA. The investigators found that, at a median 2.14 months after infection, 44% of those who had COVID-19 vs. 12% of those who were COVID negative had a relapse. Finally, a case report noted a patient with preexisting AA whose condition worsened following COVID infection.
The findings suggest that AA “could be a dermatological manifestation of COVID-19, with cases most often appearing 1-2 months following infection,” the authors wrote. “However, the heterogeneity of study designs and high proportion of case reports make it challenging to draw any conclusion.”
In an interview, dermatologist Brett King, MD, PhD, of the department of dermatology, Yale University, New Haven, Conn., said the review findings suggest that “there is little concern of alopecia areata following COVID infection.
Does new-onset AA happen, and are there exacerbations of preexisting disease related to COVID infection? Probably yes, but rarely.”
However, he noted that another form of alopecia, telogen effluvium (TE), is more common after COVID-19 infection. According to Dr. King, who was not involved with the systematic review, TE is typically time-limited, compared with AA’s more common chronic waxing-and-waning course.
“Distinguishing TE and AA is usually straightforward because AA typically presents with well-circumscribed patches of hair loss,” such as circular patches, “while TE manifests as diffuse hair loss,” he explained. “Rarely, however, AA does manifest diffuse hair loss without patches, similar to TE. In those cases, it may be difficult to distinguish them. A biopsy may be helpful if there is a question of the diagnosis.”
No study funding is reported. The review authors and Dr. King report no relevant disclosures.
A new
If there is a connection, it’s likely not a strong one, said study author Rachel E. Christensen, a graduate student at Rutgers Robert Wood Johnson Medical School, in an interview. “Based on the reported number of cases following COVID-19, alopecia areata appears to be low on the list of common skin manifestations of COVID-19,” she said. Of 402 articles screened from three databases in the review, only 11 were identified as related to alopecia areata (AA) and COVID-19, and only 9 of those met the study inclusion criteria. “This number alone highlights the very low number of published articles investigating this connection.”
The review was published in JAAD International.
While COVID-19 has been linked to a variety of skin conditions, a 2021 South Korean study of 7,958 cases and 218,779 controls found no connection between infection and AA even after covariates such as age, gender, and income level were taken into account. In a letter to the editor published in 2020, dermatologists in Turkey reported that the percentage of patients with AA at the dermatology outpatient clinic jumped from 0.97% in May 2019 to 1.48% in May 2020. The number of patients in each group wasn’t reported.
Systematic review
The investigators launched the systematic review to gain a wider perspective, although there are still limitations. On the one hand, Ms. Christensen said, “we do know that COVID-19, like other viruses, has been linked to various dermatological disorders.”
However, “it is difficult to tease apart whether any worsening of alopecia areata we see following COVID-19 is due to the virus itself or the increased psychological burden related to the infection or to the pandemic in general,” she said. Indeed, the authors of the report in Turkey attributed the rise in cases to stress.
For the review, the researchers analyzed studies from Italy (four), Turkey (two), Brazil (one), the United States (one), and Poland (one).
Six of the studies reported cases of new-onset AA following COVID-19 infection (seven cases; average age, 37 years; females, three). Another study was a retrospective review of 32 patients with preexisting AA who developed COVID-19; none experienced significant worsening of AA within 6 months.
The review also included a study based on a survey of 389 patients with AA. The investigators found that, at a median 2.14 months after infection, 44% of those who had COVID-19 vs. 12% of those who were COVID negative had a relapse. Finally, a case report noted a patient with preexisting AA whose condition worsened following COVID infection.
The findings suggest that AA “could be a dermatological manifestation of COVID-19, with cases most often appearing 1-2 months following infection,” the authors wrote. “However, the heterogeneity of study designs and high proportion of case reports make it challenging to draw any conclusion.”
In an interview, dermatologist Brett King, MD, PhD, of the department of dermatology, Yale University, New Haven, Conn., said the review findings suggest that “there is little concern of alopecia areata following COVID infection.
Does new-onset AA happen, and are there exacerbations of preexisting disease related to COVID infection? Probably yes, but rarely.”
However, he noted that another form of alopecia, telogen effluvium (TE), is more common after COVID-19 infection. According to Dr. King, who was not involved with the systematic review, TE is typically time-limited, compared with AA’s more common chronic waxing-and-waning course.
“Distinguishing TE and AA is usually straightforward because AA typically presents with well-circumscribed patches of hair loss,” such as circular patches, “while TE manifests as diffuse hair loss,” he explained. “Rarely, however, AA does manifest diffuse hair loss without patches, similar to TE. In those cases, it may be difficult to distinguish them. A biopsy may be helpful if there is a question of the diagnosis.”
No study funding is reported. The review authors and Dr. King report no relevant disclosures.
A new
If there is a connection, it’s likely not a strong one, said study author Rachel E. Christensen, a graduate student at Rutgers Robert Wood Johnson Medical School, in an interview. “Based on the reported number of cases following COVID-19, alopecia areata appears to be low on the list of common skin manifestations of COVID-19,” she said. Of 402 articles screened from three databases in the review, only 11 were identified as related to alopecia areata (AA) and COVID-19, and only 9 of those met the study inclusion criteria. “This number alone highlights the very low number of published articles investigating this connection.”
The review was published in JAAD International.
While COVID-19 has been linked to a variety of skin conditions, a 2021 South Korean study of 7,958 cases and 218,779 controls found no connection between infection and AA even after covariates such as age, gender, and income level were taken into account. In a letter to the editor published in 2020, dermatologists in Turkey reported that the percentage of patients with AA at the dermatology outpatient clinic jumped from 0.97% in May 2019 to 1.48% in May 2020. The number of patients in each group wasn’t reported.
Systematic review
The investigators launched the systematic review to gain a wider perspective, although there are still limitations. On the one hand, Ms. Christensen said, “we do know that COVID-19, like other viruses, has been linked to various dermatological disorders.”
However, “it is difficult to tease apart whether any worsening of alopecia areata we see following COVID-19 is due to the virus itself or the increased psychological burden related to the infection or to the pandemic in general,” she said. Indeed, the authors of the report in Turkey attributed the rise in cases to stress.
For the review, the researchers analyzed studies from Italy (four), Turkey (two), Brazil (one), the United States (one), and Poland (one).
Six of the studies reported cases of new-onset AA following COVID-19 infection (seven cases; average age, 37 years; females, three). Another study was a retrospective review of 32 patients with preexisting AA who developed COVID-19; none experienced significant worsening of AA within 6 months.
The review also included a study based on a survey of 389 patients with AA. The investigators found that, at a median 2.14 months after infection, 44% of those who had COVID-19 vs. 12% of those who were COVID negative had a relapse. Finally, a case report noted a patient with preexisting AA whose condition worsened following COVID infection.
The findings suggest that AA “could be a dermatological manifestation of COVID-19, with cases most often appearing 1-2 months following infection,” the authors wrote. “However, the heterogeneity of study designs and high proportion of case reports make it challenging to draw any conclusion.”
In an interview, dermatologist Brett King, MD, PhD, of the department of dermatology, Yale University, New Haven, Conn., said the review findings suggest that “there is little concern of alopecia areata following COVID infection.
Does new-onset AA happen, and are there exacerbations of preexisting disease related to COVID infection? Probably yes, but rarely.”
However, he noted that another form of alopecia, telogen effluvium (TE), is more common after COVID-19 infection. According to Dr. King, who was not involved with the systematic review, TE is typically time-limited, compared with AA’s more common chronic waxing-and-waning course.
“Distinguishing TE and AA is usually straightforward because AA typically presents with well-circumscribed patches of hair loss,” such as circular patches, “while TE manifests as diffuse hair loss,” he explained. “Rarely, however, AA does manifest diffuse hair loss without patches, similar to TE. In those cases, it may be difficult to distinguish them. A biopsy may be helpful if there is a question of the diagnosis.”
No study funding is reported. The review authors and Dr. King report no relevant disclosures.
FROM JAAD INTERNATIONAL
Hemophilia: There’s a new app for that
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
FROM RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
Updated perioperative guidance says when to hold antirheumatics
The American College of Rheumatology and the American Association of Hip and Knee Surgeons have released updated guidelines regarding whether to withhold drugs such as biologics and immunosuppressives for patients with inflammatory rheumatic disease who are scheduled to undergo elective total hip or knee replacement surgery.
The guidelines, published in a summary by the societies on Feb. 28, include revised and new recommendations about biologics and Janus kinase (JAK) inhibitors for patients with several types of inflammatory arthritis and systemic lupus erythematosus (SLE). In general, the guidelines recommend that the most powerful medications be withheld prior to surgery except for patients whose SLE is so severe that it threatens organs. They also recommend a shorter period of withholding drugs – 3 days instead of 7 – for JAK inhibitors.
The previous guidelines were published in 2017.
“These recommendations seek to balance flares of disease that are likely when medications are stopped vs. the risk of infection,” Susan M. Goodman, MD, a rheumatologist at the Hospital for Special Surgery, New York, and co–principal investigator of the guideline, told this news organization. “Patients and physicians may want to be either more conservative or more aggressive with their medications, depending on their personal priorities or specific medical history.”
According to Dr. Goodman, patients with inflammatory rheumatic diseases are especially likely to undergo joint replacement surgery because the conditions can damage the joints. “While the introduction of potent biologics has been linked to a decrease in surgery of soft tissues and small joints, there has been little impact on large-joint surgeries,” she said.
The risk of infection in these patients is about 50% higher than in the general population, she said. However, “it is hard to determine the magnitude of the effect of withholding medications, given the low rate of infection. In fact, using pharmaco-epidemiologic methods in large Medicare databases, no difference was seen in patients whose immunosuppressant medication infusions were close to the time of surgery compared to those patients whose medication infusions were months prior to surgery.”
The guidelines add a recommendation for the first time for apremilast (Otezla), saying that when it is administered twice daily it is okay to schedule surgery at any time.
Withholding drugs in patients with SLE
“We now recommend continuing biologics used to treat SLE – rituximab and belimumab – in patients with severe SLE but continue to recommend withholding them in less severe cases where there is little risk of organ damage,” Bryan D. Springer, MD, an orthopedic surgeon in Charlotte, N.C., first vice president of the AAHKS, and co–principal investigator of the new guidelines, told this news organization.
In severe SLE cases, the guidelines recommend timing total joint replacement surgery for 4-6 months after the latest IV dose of rituximab (Rituxan), which is given every 4-6 months. For patients taking belimumab (Benlysta), time surgery anytime when weekly subcutaneous doses are administered or at week 4 when monthly IV doses are given.
The guidelines also make recommendations regarding two new drugs for the treatment of severe SLE:
- Anifrolumab (Saphnelo): Time surgery at week 4 when IV treatment is given every 4 weeks.
- Voclosporin (Lupkynis): Continue doses when they’re given twice daily.
An ACR statement cautions that there are no published, peer-reviewed data regarding the use of these two drugs prior to total joint surgery. “The medications do increase the risk of infection,” the statement says, “and therefore their use in patients with severe SLE would merit review by the treating rheumatologist in consideration of surgery.”
Timing of stopping and restarting medication
The guidelines also recommend that certain drugs be withheld for patients with rheumatoid arthritis, ankylosing spondylitis, or any type of SLE and then “restarting the antirheumatic therapy once the wound shows evidence of healing, any sutures/staples are out, there is no significant swelling, erythema, or drainage, and there is no ongoing nonsurgical site infection, which is typically about 14 days.”
In regard to biologics, “we continue to recommend withholding biologic medications in patients with inflammatory arthritis, withholding the medication for a dosing cycle prior to surgery, and scheduling the surgery after that dose would be due,” Dr. Springer said. “For example, if a patient takes the medication every 4 weeks, the patient would withhold the dose of the medication and schedule surgery in the 5th week.”
The new recommendations for biologics suggest scheduling surgery at week 5 when the interleukin (IL)-17 inhibitor ixekizumab (Taltz) is given once every 4 weeks and at week 9 when the IL-23 inhibitor guselkumab (Tremfya) is given every 8 weeks.
The guidelines also revise the previous recommendation about tofacitinib (Xeljanz): Surgery should be scheduled on day 4 when the drug is given once or twice daily. New recommendations for fellow JAK inhibitors baricitinib (Olumiant, daily) and upadacitinib (Rinvoq, daily) are the same: Withhold for 3 days prior to surgery and perform surgery on the 4th day.
“We shortened the time between the last dose of JAK inhibitors and surgery to 3 days from 7 based on trial data demonstrating early flares when the drug was withheld, suggesting the immunosuppressant effect wears off sooner than we previously thought,” Dr. Springer said.
The guidelines caution that the recommendations for JAK inhibitors are for infection risk but do not consider the risk of cardiac events or venous thromboembolism.
In patients with nonsevere SLE, the guidelines revise the recommendations for mycophenolate mofetil (twice daily), cyclosporine (twice daily), and tacrolimus (twice daily, IV and oral). The new advice is to withhold the drugs for 1 week after last dose prior to surgery. New recommendations offer the same advice for belimumab, both IV and subcutaneous: Withhold for 1 week after last dose prior to surgery.
The board of the ACR approved the guidelines summary; the full manuscript has been submitted for peer review with an eye toward later publication in the journals Arthritis and Rheumatology and Arthritis Care and Research.
The ACR and AAHKS funded the guidelines. Dr. Goodman and Dr. Springer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The American College of Rheumatology and the American Association of Hip and Knee Surgeons have released updated guidelines regarding whether to withhold drugs such as biologics and immunosuppressives for patients with inflammatory rheumatic disease who are scheduled to undergo elective total hip or knee replacement surgery.
The guidelines, published in a summary by the societies on Feb. 28, include revised and new recommendations about biologics and Janus kinase (JAK) inhibitors for patients with several types of inflammatory arthritis and systemic lupus erythematosus (SLE). In general, the guidelines recommend that the most powerful medications be withheld prior to surgery except for patients whose SLE is so severe that it threatens organs. They also recommend a shorter period of withholding drugs – 3 days instead of 7 – for JAK inhibitors.
The previous guidelines were published in 2017.
“These recommendations seek to balance flares of disease that are likely when medications are stopped vs. the risk of infection,” Susan M. Goodman, MD, a rheumatologist at the Hospital for Special Surgery, New York, and co–principal investigator of the guideline, told this news organization. “Patients and physicians may want to be either more conservative or more aggressive with their medications, depending on their personal priorities or specific medical history.”
According to Dr. Goodman, patients with inflammatory rheumatic diseases are especially likely to undergo joint replacement surgery because the conditions can damage the joints. “While the introduction of potent biologics has been linked to a decrease in surgery of soft tissues and small joints, there has been little impact on large-joint surgeries,” she said.
The risk of infection in these patients is about 50% higher than in the general population, she said. However, “it is hard to determine the magnitude of the effect of withholding medications, given the low rate of infection. In fact, using pharmaco-epidemiologic methods in large Medicare databases, no difference was seen in patients whose immunosuppressant medication infusions were close to the time of surgery compared to those patients whose medication infusions were months prior to surgery.”
The guidelines add a recommendation for the first time for apremilast (Otezla), saying that when it is administered twice daily it is okay to schedule surgery at any time.
Withholding drugs in patients with SLE
“We now recommend continuing biologics used to treat SLE – rituximab and belimumab – in patients with severe SLE but continue to recommend withholding them in less severe cases where there is little risk of organ damage,” Bryan D. Springer, MD, an orthopedic surgeon in Charlotte, N.C., first vice president of the AAHKS, and co–principal investigator of the new guidelines, told this news organization.
In severe SLE cases, the guidelines recommend timing total joint replacement surgery for 4-6 months after the latest IV dose of rituximab (Rituxan), which is given every 4-6 months. For patients taking belimumab (Benlysta), time surgery anytime when weekly subcutaneous doses are administered or at week 4 when monthly IV doses are given.
The guidelines also make recommendations regarding two new drugs for the treatment of severe SLE:
- Anifrolumab (Saphnelo): Time surgery at week 4 when IV treatment is given every 4 weeks.
- Voclosporin (Lupkynis): Continue doses when they’re given twice daily.
An ACR statement cautions that there are no published, peer-reviewed data regarding the use of these two drugs prior to total joint surgery. “The medications do increase the risk of infection,” the statement says, “and therefore their use in patients with severe SLE would merit review by the treating rheumatologist in consideration of surgery.”
Timing of stopping and restarting medication
The guidelines also recommend that certain drugs be withheld for patients with rheumatoid arthritis, ankylosing spondylitis, or any type of SLE and then “restarting the antirheumatic therapy once the wound shows evidence of healing, any sutures/staples are out, there is no significant swelling, erythema, or drainage, and there is no ongoing nonsurgical site infection, which is typically about 14 days.”
In regard to biologics, “we continue to recommend withholding biologic medications in patients with inflammatory arthritis, withholding the medication for a dosing cycle prior to surgery, and scheduling the surgery after that dose would be due,” Dr. Springer said. “For example, if a patient takes the medication every 4 weeks, the patient would withhold the dose of the medication and schedule surgery in the 5th week.”
The new recommendations for biologics suggest scheduling surgery at week 5 when the interleukin (IL)-17 inhibitor ixekizumab (Taltz) is given once every 4 weeks and at week 9 when the IL-23 inhibitor guselkumab (Tremfya) is given every 8 weeks.
The guidelines also revise the previous recommendation about tofacitinib (Xeljanz): Surgery should be scheduled on day 4 when the drug is given once or twice daily. New recommendations for fellow JAK inhibitors baricitinib (Olumiant, daily) and upadacitinib (Rinvoq, daily) are the same: Withhold for 3 days prior to surgery and perform surgery on the 4th day.
“We shortened the time between the last dose of JAK inhibitors and surgery to 3 days from 7 based on trial data demonstrating early flares when the drug was withheld, suggesting the immunosuppressant effect wears off sooner than we previously thought,” Dr. Springer said.
The guidelines caution that the recommendations for JAK inhibitors are for infection risk but do not consider the risk of cardiac events or venous thromboembolism.
In patients with nonsevere SLE, the guidelines revise the recommendations for mycophenolate mofetil (twice daily), cyclosporine (twice daily), and tacrolimus (twice daily, IV and oral). The new advice is to withhold the drugs for 1 week after last dose prior to surgery. New recommendations offer the same advice for belimumab, both IV and subcutaneous: Withhold for 1 week after last dose prior to surgery.
The board of the ACR approved the guidelines summary; the full manuscript has been submitted for peer review with an eye toward later publication in the journals Arthritis and Rheumatology and Arthritis Care and Research.
The ACR and AAHKS funded the guidelines. Dr. Goodman and Dr. Springer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The American College of Rheumatology and the American Association of Hip and Knee Surgeons have released updated guidelines regarding whether to withhold drugs such as biologics and immunosuppressives for patients with inflammatory rheumatic disease who are scheduled to undergo elective total hip or knee replacement surgery.
The guidelines, published in a summary by the societies on Feb. 28, include revised and new recommendations about biologics and Janus kinase (JAK) inhibitors for patients with several types of inflammatory arthritis and systemic lupus erythematosus (SLE). In general, the guidelines recommend that the most powerful medications be withheld prior to surgery except for patients whose SLE is so severe that it threatens organs. They also recommend a shorter period of withholding drugs – 3 days instead of 7 – for JAK inhibitors.
The previous guidelines were published in 2017.
“These recommendations seek to balance flares of disease that are likely when medications are stopped vs. the risk of infection,” Susan M. Goodman, MD, a rheumatologist at the Hospital for Special Surgery, New York, and co–principal investigator of the guideline, told this news organization. “Patients and physicians may want to be either more conservative or more aggressive with their medications, depending on their personal priorities or specific medical history.”
According to Dr. Goodman, patients with inflammatory rheumatic diseases are especially likely to undergo joint replacement surgery because the conditions can damage the joints. “While the introduction of potent biologics has been linked to a decrease in surgery of soft tissues and small joints, there has been little impact on large-joint surgeries,” she said.
The risk of infection in these patients is about 50% higher than in the general population, she said. However, “it is hard to determine the magnitude of the effect of withholding medications, given the low rate of infection. In fact, using pharmaco-epidemiologic methods in large Medicare databases, no difference was seen in patients whose immunosuppressant medication infusions were close to the time of surgery compared to those patients whose medication infusions were months prior to surgery.”
The guidelines add a recommendation for the first time for apremilast (Otezla), saying that when it is administered twice daily it is okay to schedule surgery at any time.
Withholding drugs in patients with SLE
“We now recommend continuing biologics used to treat SLE – rituximab and belimumab – in patients with severe SLE but continue to recommend withholding them in less severe cases where there is little risk of organ damage,” Bryan D. Springer, MD, an orthopedic surgeon in Charlotte, N.C., first vice president of the AAHKS, and co–principal investigator of the new guidelines, told this news organization.
In severe SLE cases, the guidelines recommend timing total joint replacement surgery for 4-6 months after the latest IV dose of rituximab (Rituxan), which is given every 4-6 months. For patients taking belimumab (Benlysta), time surgery anytime when weekly subcutaneous doses are administered or at week 4 when monthly IV doses are given.
The guidelines also make recommendations regarding two new drugs for the treatment of severe SLE:
- Anifrolumab (Saphnelo): Time surgery at week 4 when IV treatment is given every 4 weeks.
- Voclosporin (Lupkynis): Continue doses when they’re given twice daily.
An ACR statement cautions that there are no published, peer-reviewed data regarding the use of these two drugs prior to total joint surgery. “The medications do increase the risk of infection,” the statement says, “and therefore their use in patients with severe SLE would merit review by the treating rheumatologist in consideration of surgery.”
Timing of stopping and restarting medication
The guidelines also recommend that certain drugs be withheld for patients with rheumatoid arthritis, ankylosing spondylitis, or any type of SLE and then “restarting the antirheumatic therapy once the wound shows evidence of healing, any sutures/staples are out, there is no significant swelling, erythema, or drainage, and there is no ongoing nonsurgical site infection, which is typically about 14 days.”
In regard to biologics, “we continue to recommend withholding biologic medications in patients with inflammatory arthritis, withholding the medication for a dosing cycle prior to surgery, and scheduling the surgery after that dose would be due,” Dr. Springer said. “For example, if a patient takes the medication every 4 weeks, the patient would withhold the dose of the medication and schedule surgery in the 5th week.”
The new recommendations for biologics suggest scheduling surgery at week 5 when the interleukin (IL)-17 inhibitor ixekizumab (Taltz) is given once every 4 weeks and at week 9 when the IL-23 inhibitor guselkumab (Tremfya) is given every 8 weeks.
The guidelines also revise the previous recommendation about tofacitinib (Xeljanz): Surgery should be scheduled on day 4 when the drug is given once or twice daily. New recommendations for fellow JAK inhibitors baricitinib (Olumiant, daily) and upadacitinib (Rinvoq, daily) are the same: Withhold for 3 days prior to surgery and perform surgery on the 4th day.
“We shortened the time between the last dose of JAK inhibitors and surgery to 3 days from 7 based on trial data demonstrating early flares when the drug was withheld, suggesting the immunosuppressant effect wears off sooner than we previously thought,” Dr. Springer said.
The guidelines caution that the recommendations for JAK inhibitors are for infection risk but do not consider the risk of cardiac events or venous thromboembolism.
In patients with nonsevere SLE, the guidelines revise the recommendations for mycophenolate mofetil (twice daily), cyclosporine (twice daily), and tacrolimus (twice daily, IV and oral). The new advice is to withhold the drugs for 1 week after last dose prior to surgery. New recommendations offer the same advice for belimumab, both IV and subcutaneous: Withhold for 1 week after last dose prior to surgery.
The board of the ACR approved the guidelines summary; the full manuscript has been submitted for peer review with an eye toward later publication in the journals Arthritis and Rheumatology and Arthritis Care and Research.
The ACR and AAHKS funded the guidelines. Dr. Goodman and Dr. Springer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Analysis questions tocilizumab in ventilated COVID patients
A new statistical analysis of an existing meta-analysis reaffirms a finding that hospitalized patients with COVID-19 who are on simple oxygen or noninvasive ventilation can benefit from treatment with the arthritis drug tocilizumab (Actemra) in conjunction with corticosteroids. But the report also casts doubt on the effectiveness of tocilizumab in patients who are on ventilators.
“Clinicians should prescribe steroids and tocilizumab for hospitalized patients needing simple oxygen or noninvasive ventilation,” epidemiologist and study coauthor James (Jay) Brophy, MD, PhD, of McGill University, Montreal, said in an interview. “Further research is required to answer the question of whether tocilizumab is beneficial in patients requiring invasive ventilation, and consideration of participation in further tocilizumab studies seems reasonable.”
The new analysis was published Feb. 28, 2022, in JAMA Network Open.
The initial meta-analysis, published in 2021 in JAMA, was conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. It analyzed the results of 27 randomized trials that explored the use of interleukin-6 antagonists, including tocilizumab, and found that “28-day all-cause mortality was lower among patients who received IL-6 antagonists, compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary ORs for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids versus 1.09 without administration of corticosteroids.”
For the new report, researchers conducted a Bayesian statistical analysis of 15 studies within the meta-analysis that specifically examined the use of the rheumatoid arthritis drug tocilizumab. “Bayesian analysis allows one to make direct probability statements regarding the exact magnitude and the certainty of any benefit,” Dr. Brophy said. “This provides clinicians with the information they require to make well-informed decisions.”
The analysis estimated that the probability of a “clinically meaningful association” (absolute mortality risk difference, >1%) because of use of tocilizumab was higher than 95% in patients receiving simple oxygen and higher than 90% in those receiving noninvasive ventilation. But the probability was only about 67% higher in those receiving invasive mechanical ventilation.
Also, the researchers estimated that about 72% of future tocilizumab studies in patients on invasive mechanical ventilation would show a benefit.
The new analysis findings don’t add much to existing knowledge, said nephrologist David E. Leaf, MD, MMSc, of Harvard Medical School, Boston, who’s studied tocilizumab in COVID-19.
“The signal seems to be consistent that there is a greater benefit of tocilizumab in less ill patients than those who are more ill – e.g., those who are receiving invasive mechanical ventilation,” Dr. Leaf said in an interview. “This is interesting because in clinical practice the opposite approach is often undertaken, with tocilizumab use only being used in the sickest patients, even though the patients most likely to benefit seem to be those who are less ill.”
Clinically, he said, “hospitalized patients with COVID-19 should receive tocilizumab unless they have a clear contraindication and assuming it can be administered relatively early in their disease course. Earlier administration, before the onset of irreversible organ injury, is likely to have greater benefit.”
Dr. Leaf also noted it’s unknown whether the drug is helpful in several groups – patients presenting later in the course of COVID-19 illness, patients with additional infections, and immunocompromised patients.
It’s also not clear if tocilizumab benefits patients with lower levels of C-reactive protein, Shruti Gupta, MD, MPH, a nephrologist at Brigham and Women’s Hospital in Boston, said in an interview. The RECOVERY trial, for example, limited subjects to those with C-reactive protein of at least 75 mg/L.
Dr. Leaf and Dr. Gupta coauthored a 2021 cohort study analyzing mortality rates in patients with COVID-19 who were treated with tocilizumab versus those who were not.
No study funding was reported. Dr. Brophy, Dr. Leaf, and Dr. Gupta disclosed no relevant financial relationships. One study author reported participating in one of the randomized clinical trials included in the analysis.
A version of this article first appeared on Medscape.com.
A new statistical analysis of an existing meta-analysis reaffirms a finding that hospitalized patients with COVID-19 who are on simple oxygen or noninvasive ventilation can benefit from treatment with the arthritis drug tocilizumab (Actemra) in conjunction with corticosteroids. But the report also casts doubt on the effectiveness of tocilizumab in patients who are on ventilators.
“Clinicians should prescribe steroids and tocilizumab for hospitalized patients needing simple oxygen or noninvasive ventilation,” epidemiologist and study coauthor James (Jay) Brophy, MD, PhD, of McGill University, Montreal, said in an interview. “Further research is required to answer the question of whether tocilizumab is beneficial in patients requiring invasive ventilation, and consideration of participation in further tocilizumab studies seems reasonable.”
The new analysis was published Feb. 28, 2022, in JAMA Network Open.
The initial meta-analysis, published in 2021 in JAMA, was conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. It analyzed the results of 27 randomized trials that explored the use of interleukin-6 antagonists, including tocilizumab, and found that “28-day all-cause mortality was lower among patients who received IL-6 antagonists, compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary ORs for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids versus 1.09 without administration of corticosteroids.”
For the new report, researchers conducted a Bayesian statistical analysis of 15 studies within the meta-analysis that specifically examined the use of the rheumatoid arthritis drug tocilizumab. “Bayesian analysis allows one to make direct probability statements regarding the exact magnitude and the certainty of any benefit,” Dr. Brophy said. “This provides clinicians with the information they require to make well-informed decisions.”
The analysis estimated that the probability of a “clinically meaningful association” (absolute mortality risk difference, >1%) because of use of tocilizumab was higher than 95% in patients receiving simple oxygen and higher than 90% in those receiving noninvasive ventilation. But the probability was only about 67% higher in those receiving invasive mechanical ventilation.
Also, the researchers estimated that about 72% of future tocilizumab studies in patients on invasive mechanical ventilation would show a benefit.
The new analysis findings don’t add much to existing knowledge, said nephrologist David E. Leaf, MD, MMSc, of Harvard Medical School, Boston, who’s studied tocilizumab in COVID-19.
“The signal seems to be consistent that there is a greater benefit of tocilizumab in less ill patients than those who are more ill – e.g., those who are receiving invasive mechanical ventilation,” Dr. Leaf said in an interview. “This is interesting because in clinical practice the opposite approach is often undertaken, with tocilizumab use only being used in the sickest patients, even though the patients most likely to benefit seem to be those who are less ill.”
Clinically, he said, “hospitalized patients with COVID-19 should receive tocilizumab unless they have a clear contraindication and assuming it can be administered relatively early in their disease course. Earlier administration, before the onset of irreversible organ injury, is likely to have greater benefit.”
Dr. Leaf also noted it’s unknown whether the drug is helpful in several groups – patients presenting later in the course of COVID-19 illness, patients with additional infections, and immunocompromised patients.
It’s also not clear if tocilizumab benefits patients with lower levels of C-reactive protein, Shruti Gupta, MD, MPH, a nephrologist at Brigham and Women’s Hospital in Boston, said in an interview. The RECOVERY trial, for example, limited subjects to those with C-reactive protein of at least 75 mg/L.
Dr. Leaf and Dr. Gupta coauthored a 2021 cohort study analyzing mortality rates in patients with COVID-19 who were treated with tocilizumab versus those who were not.
No study funding was reported. Dr. Brophy, Dr. Leaf, and Dr. Gupta disclosed no relevant financial relationships. One study author reported participating in one of the randomized clinical trials included in the analysis.
A version of this article first appeared on Medscape.com.
A new statistical analysis of an existing meta-analysis reaffirms a finding that hospitalized patients with COVID-19 who are on simple oxygen or noninvasive ventilation can benefit from treatment with the arthritis drug tocilizumab (Actemra) in conjunction with corticosteroids. But the report also casts doubt on the effectiveness of tocilizumab in patients who are on ventilators.
“Clinicians should prescribe steroids and tocilizumab for hospitalized patients needing simple oxygen or noninvasive ventilation,” epidemiologist and study coauthor James (Jay) Brophy, MD, PhD, of McGill University, Montreal, said in an interview. “Further research is required to answer the question of whether tocilizumab is beneficial in patients requiring invasive ventilation, and consideration of participation in further tocilizumab studies seems reasonable.”
The new analysis was published Feb. 28, 2022, in JAMA Network Open.
The initial meta-analysis, published in 2021 in JAMA, was conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. It analyzed the results of 27 randomized trials that explored the use of interleukin-6 antagonists, including tocilizumab, and found that “28-day all-cause mortality was lower among patients who received IL-6 antagonists, compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary ORs for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids versus 1.09 without administration of corticosteroids.”
For the new report, researchers conducted a Bayesian statistical analysis of 15 studies within the meta-analysis that specifically examined the use of the rheumatoid arthritis drug tocilizumab. “Bayesian analysis allows one to make direct probability statements regarding the exact magnitude and the certainty of any benefit,” Dr. Brophy said. “This provides clinicians with the information they require to make well-informed decisions.”
The analysis estimated that the probability of a “clinically meaningful association” (absolute mortality risk difference, >1%) because of use of tocilizumab was higher than 95% in patients receiving simple oxygen and higher than 90% in those receiving noninvasive ventilation. But the probability was only about 67% higher in those receiving invasive mechanical ventilation.
Also, the researchers estimated that about 72% of future tocilizumab studies in patients on invasive mechanical ventilation would show a benefit.
The new analysis findings don’t add much to existing knowledge, said nephrologist David E. Leaf, MD, MMSc, of Harvard Medical School, Boston, who’s studied tocilizumab in COVID-19.
“The signal seems to be consistent that there is a greater benefit of tocilizumab in less ill patients than those who are more ill – e.g., those who are receiving invasive mechanical ventilation,” Dr. Leaf said in an interview. “This is interesting because in clinical practice the opposite approach is often undertaken, with tocilizumab use only being used in the sickest patients, even though the patients most likely to benefit seem to be those who are less ill.”
Clinically, he said, “hospitalized patients with COVID-19 should receive tocilizumab unless they have a clear contraindication and assuming it can be administered relatively early in their disease course. Earlier administration, before the onset of irreversible organ injury, is likely to have greater benefit.”
Dr. Leaf also noted it’s unknown whether the drug is helpful in several groups – patients presenting later in the course of COVID-19 illness, patients with additional infections, and immunocompromised patients.
It’s also not clear if tocilizumab benefits patients with lower levels of C-reactive protein, Shruti Gupta, MD, MPH, a nephrologist at Brigham and Women’s Hospital in Boston, said in an interview. The RECOVERY trial, for example, limited subjects to those with C-reactive protein of at least 75 mg/L.
Dr. Leaf and Dr. Gupta coauthored a 2021 cohort study analyzing mortality rates in patients with COVID-19 who were treated with tocilizumab versus those who were not.
No study funding was reported. Dr. Brophy, Dr. Leaf, and Dr. Gupta disclosed no relevant financial relationships. One study author reported participating in one of the randomized clinical trials included in the analysis.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Researchers tout new CLL prognostic tool
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
FROM BLOOD ADVANCES
Gene therapy: A ‘one and done’ hemophilia B treatment?
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
REPORTING FROM EAHAD
OTC melatonin supplement use rises fivefold over 20 years
, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.
The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”
The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”
For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.
The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.
“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”
Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.
The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.
Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.
According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”
Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”
The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.
Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.
A version of this article first appeared on Medscape.com.
, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.
The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”
The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”
For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.
The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.
“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”
Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.
The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.
Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.
According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”
Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”
The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.
Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.
A version of this article first appeared on Medscape.com.
, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.
The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”
The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”
For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.
The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.
“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”
Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.
The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.
Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.
According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”
Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”
The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.
Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.
A version of this article first appeared on Medscape.com.
FROM JAMA
Hormone therapy in transgender teens linked to better adult mental health
In another salvo in the heated debate over treatment for kids who believe they’re transgender, a study published in PLoS One suggests that transgender adults who received hormone therapy as teenagers are mentally healthier in a pair of ways than those who didn’t.
The study, which only looks at transgender adults, doesn’t confirm that hormone therapy in childhood is a beneficial treatment. Still, “we found that for all age groups, access to [adolescent] gender-affirming hormone initiation was associated with lower odds of past-year suicidal ideation and past-month severe psychological distress measured in adulthood,” said lead author Jack Turban, MD, chief fellow in child and adolescent psychiatry at Stanford (Calif.) University, in an interview. “We also found better mental-health outcomes for those who started gender-affirming hormones as adolescents when compared to those who didn’t start them until they were adults.”
The use of hormone treatment and puberty blockers by transgender teens is extremely controversial. Critics say the treatments are harmful and unnecessary, and Republican politicians are trying to ban their use in some states. Last spring, Arkansas became the first state to ban the treatments. The law is on hold amid a legal challenge.
The researchers launched the study to gain more insight into the impact of hormone therapy on children. “There have been several longitudinal studies showing that mental health improves following gender-affirming medical care for transgender youth, but there has been less research looking at the relationship between when these medications are started and adult mental health outcomes,” Dr. Turban said. “This is the first study to look at various ages of initiation of gender-affirming hormones and compare outcomes between those who started gender-affirming hormones during adolescence and those who did not start them until adulthood.”
For the new study, the authors analyzed the findings of the 2015 U.S. Transgender Survey of 27,715 adults and focused on 21,598 who said they’d wanted hormone therapy (40% aged 18-24, 83% White, 35% transgender male, 41% transgender female, with the rest using other terms such as “queer” or “nonbinary” to describe themselves).
Of these subjects, 41.0% never received hormone therapy, 0.6% underwent therapy in early adolescence, 1.7% received it in late adolescence, and 56.8% got it as adults.
The researchers made various adjustments for confounders – age, partnership status, employment status, K-12 harassment, and experience of gender identity conversion efforts. Those who received hormone therapy had lower odds of past-year suicidal ideation vs. those who didn’t: adjusted odds ratio, 0.4; 95% confidence interval, 0.2-0.6; P < .0001 for therapy that occurred from age 14 to 15, aOR, 0.5; 95% CI, 0.4-0.7; P < .0001, for therapy that occurred from age 16 to 17, and aOR, 0.8; 95% CI, 0.7-0.8; P < .0001 for therapy that occurred in adulthood.
However, there was no statistically significant link between hormone therapy and past-year suicidal ideation with a plan or past-year suicide attempt.
The study also found lower rates of past-month severe psychological distress: aOR. 0.3; 95% CI, 0.2-0.4; P < .0001 for therapy from age 14 to 15, aOR, 0.3; 95% CI, 0.3-0.4; P < .0001 for therapy from age 16 to 17, and aOR, 0.6 (95% CI, 0.5-0.6; P < .0001) for therapy in adulthood.
There was no statistically significant link between hormone therapy and past-month binge drinking or lifetime illicit drug use.
“The findings indicate that clinicians caring for adolescents need to be properly trained in gender-affirming medical care, including hormone therapy, in order to help promote good mental health outcomes for transgender people. Comprehensive training in gender-affirming care is currently not part of standard medical education curricula,” said study coauthor Alex Keuroghlian, MD, MPH, director of the National LGBTQIA+ Health Education Center at the Fenway Institute and associate professor of psychiatry at Harvard Medical School, Boston, in an interview.
The study has limitations. The survey population doesn’t include anyone who committed suicide, nor does it include people who had gender dysphoria as children but didn’t go on to identify as transgender as adults. It is also retrospective. “There is a general consensus that, given the data we have so far, it would be unethical to conduct a randomized controlled trial in this space,” said study lead author Dr. Turban.
Several critics of hormone therapy in teens support a psychotherapy-based approach to gender dysphoria that considers whether other factors are at play than transgender orientation. They’ve united to attack research based on the 2015 transgender survey. In a 2021 report in Archives of Sexual Behavior, they called it “a highly skewed sample” and objected to “a conflation of ethical nonaffirmative psychotherapy with conversion therapy.”
In an interview, one of the critics – developmental psychologist and retired University of Sydney professor Dianna Kenny, PhD – said the new study’s “serious problem of recall bias” about hormone therapy in the survey is “insurmountable.” The survey, she said, also fails to explore why participants who wanted hormone therapy didn’t get it.
Dr. Kenny, who believes all hormone therapy in teens with gender dysphoria outside of clinical trials is inappropriate, also pointed out that hormone therapy has many side effects. She added that young people with gender dysphoria often “realize through a process of cognitive and psychosocial maturation that they were not ‘genuinely’ trans but suffering from other conditions that needed treatment – e.g., internalized homophobia, trauma, including sexual abuse, attention-deficit/hyperactivity disorder, autism spectrum disorder, etc.”
No specific funding is reported, although two of the authors report receiving various grants, fellowship and research funding. Dr. Turban discloses textbook royalties from Springer Nature and expert witness payments from the ACLU. Dr. Keuroghlian discloses textbook royalties from McGraw Hill. Dr. Kenny reports no disclosures.
In another salvo in the heated debate over treatment for kids who believe they’re transgender, a study published in PLoS One suggests that transgender adults who received hormone therapy as teenagers are mentally healthier in a pair of ways than those who didn’t.
The study, which only looks at transgender adults, doesn’t confirm that hormone therapy in childhood is a beneficial treatment. Still, “we found that for all age groups, access to [adolescent] gender-affirming hormone initiation was associated with lower odds of past-year suicidal ideation and past-month severe psychological distress measured in adulthood,” said lead author Jack Turban, MD, chief fellow in child and adolescent psychiatry at Stanford (Calif.) University, in an interview. “We also found better mental-health outcomes for those who started gender-affirming hormones as adolescents when compared to those who didn’t start them until they were adults.”
The use of hormone treatment and puberty blockers by transgender teens is extremely controversial. Critics say the treatments are harmful and unnecessary, and Republican politicians are trying to ban their use in some states. Last spring, Arkansas became the first state to ban the treatments. The law is on hold amid a legal challenge.
The researchers launched the study to gain more insight into the impact of hormone therapy on children. “There have been several longitudinal studies showing that mental health improves following gender-affirming medical care for transgender youth, but there has been less research looking at the relationship between when these medications are started and adult mental health outcomes,” Dr. Turban said. “This is the first study to look at various ages of initiation of gender-affirming hormones and compare outcomes between those who started gender-affirming hormones during adolescence and those who did not start them until adulthood.”
For the new study, the authors analyzed the findings of the 2015 U.S. Transgender Survey of 27,715 adults and focused on 21,598 who said they’d wanted hormone therapy (40% aged 18-24, 83% White, 35% transgender male, 41% transgender female, with the rest using other terms such as “queer” or “nonbinary” to describe themselves).
Of these subjects, 41.0% never received hormone therapy, 0.6% underwent therapy in early adolescence, 1.7% received it in late adolescence, and 56.8% got it as adults.
The researchers made various adjustments for confounders – age, partnership status, employment status, K-12 harassment, and experience of gender identity conversion efforts. Those who received hormone therapy had lower odds of past-year suicidal ideation vs. those who didn’t: adjusted odds ratio, 0.4; 95% confidence interval, 0.2-0.6; P < .0001 for therapy that occurred from age 14 to 15, aOR, 0.5; 95% CI, 0.4-0.7; P < .0001, for therapy that occurred from age 16 to 17, and aOR, 0.8; 95% CI, 0.7-0.8; P < .0001 for therapy that occurred in adulthood.
However, there was no statistically significant link between hormone therapy and past-year suicidal ideation with a plan or past-year suicide attempt.
The study also found lower rates of past-month severe psychological distress: aOR. 0.3; 95% CI, 0.2-0.4; P < .0001 for therapy from age 14 to 15, aOR, 0.3; 95% CI, 0.3-0.4; P < .0001 for therapy from age 16 to 17, and aOR, 0.6 (95% CI, 0.5-0.6; P < .0001) for therapy in adulthood.
There was no statistically significant link between hormone therapy and past-month binge drinking or lifetime illicit drug use.
“The findings indicate that clinicians caring for adolescents need to be properly trained in gender-affirming medical care, including hormone therapy, in order to help promote good mental health outcomes for transgender people. Comprehensive training in gender-affirming care is currently not part of standard medical education curricula,” said study coauthor Alex Keuroghlian, MD, MPH, director of the National LGBTQIA+ Health Education Center at the Fenway Institute and associate professor of psychiatry at Harvard Medical School, Boston, in an interview.
The study has limitations. The survey population doesn’t include anyone who committed suicide, nor does it include people who had gender dysphoria as children but didn’t go on to identify as transgender as adults. It is also retrospective. “There is a general consensus that, given the data we have so far, it would be unethical to conduct a randomized controlled trial in this space,” said study lead author Dr. Turban.
Several critics of hormone therapy in teens support a psychotherapy-based approach to gender dysphoria that considers whether other factors are at play than transgender orientation. They’ve united to attack research based on the 2015 transgender survey. In a 2021 report in Archives of Sexual Behavior, they called it “a highly skewed sample” and objected to “a conflation of ethical nonaffirmative psychotherapy with conversion therapy.”
In an interview, one of the critics – developmental psychologist and retired University of Sydney professor Dianna Kenny, PhD – said the new study’s “serious problem of recall bias” about hormone therapy in the survey is “insurmountable.” The survey, she said, also fails to explore why participants who wanted hormone therapy didn’t get it.
Dr. Kenny, who believes all hormone therapy in teens with gender dysphoria outside of clinical trials is inappropriate, also pointed out that hormone therapy has many side effects. She added that young people with gender dysphoria often “realize through a process of cognitive and psychosocial maturation that they were not ‘genuinely’ trans but suffering from other conditions that needed treatment – e.g., internalized homophobia, trauma, including sexual abuse, attention-deficit/hyperactivity disorder, autism spectrum disorder, etc.”
No specific funding is reported, although two of the authors report receiving various grants, fellowship and research funding. Dr. Turban discloses textbook royalties from Springer Nature and expert witness payments from the ACLU. Dr. Keuroghlian discloses textbook royalties from McGraw Hill. Dr. Kenny reports no disclosures.
In another salvo in the heated debate over treatment for kids who believe they’re transgender, a study published in PLoS One suggests that transgender adults who received hormone therapy as teenagers are mentally healthier in a pair of ways than those who didn’t.
The study, which only looks at transgender adults, doesn’t confirm that hormone therapy in childhood is a beneficial treatment. Still, “we found that for all age groups, access to [adolescent] gender-affirming hormone initiation was associated with lower odds of past-year suicidal ideation and past-month severe psychological distress measured in adulthood,” said lead author Jack Turban, MD, chief fellow in child and adolescent psychiatry at Stanford (Calif.) University, in an interview. “We also found better mental-health outcomes for those who started gender-affirming hormones as adolescents when compared to those who didn’t start them until they were adults.”
The use of hormone treatment and puberty blockers by transgender teens is extremely controversial. Critics say the treatments are harmful and unnecessary, and Republican politicians are trying to ban their use in some states. Last spring, Arkansas became the first state to ban the treatments. The law is on hold amid a legal challenge.
The researchers launched the study to gain more insight into the impact of hormone therapy on children. “There have been several longitudinal studies showing that mental health improves following gender-affirming medical care for transgender youth, but there has been less research looking at the relationship between when these medications are started and adult mental health outcomes,” Dr. Turban said. “This is the first study to look at various ages of initiation of gender-affirming hormones and compare outcomes between those who started gender-affirming hormones during adolescence and those who did not start them until adulthood.”
For the new study, the authors analyzed the findings of the 2015 U.S. Transgender Survey of 27,715 adults and focused on 21,598 who said they’d wanted hormone therapy (40% aged 18-24, 83% White, 35% transgender male, 41% transgender female, with the rest using other terms such as “queer” or “nonbinary” to describe themselves).
Of these subjects, 41.0% never received hormone therapy, 0.6% underwent therapy in early adolescence, 1.7% received it in late adolescence, and 56.8% got it as adults.
The researchers made various adjustments for confounders – age, partnership status, employment status, K-12 harassment, and experience of gender identity conversion efforts. Those who received hormone therapy had lower odds of past-year suicidal ideation vs. those who didn’t: adjusted odds ratio, 0.4; 95% confidence interval, 0.2-0.6; P < .0001 for therapy that occurred from age 14 to 15, aOR, 0.5; 95% CI, 0.4-0.7; P < .0001, for therapy that occurred from age 16 to 17, and aOR, 0.8; 95% CI, 0.7-0.8; P < .0001 for therapy that occurred in adulthood.
However, there was no statistically significant link between hormone therapy and past-year suicidal ideation with a plan or past-year suicide attempt.
The study also found lower rates of past-month severe psychological distress: aOR. 0.3; 95% CI, 0.2-0.4; P < .0001 for therapy from age 14 to 15, aOR, 0.3; 95% CI, 0.3-0.4; P < .0001 for therapy from age 16 to 17, and aOR, 0.6 (95% CI, 0.5-0.6; P < .0001) for therapy in adulthood.
There was no statistically significant link between hormone therapy and past-month binge drinking or lifetime illicit drug use.
“The findings indicate that clinicians caring for adolescents need to be properly trained in gender-affirming medical care, including hormone therapy, in order to help promote good mental health outcomes for transgender people. Comprehensive training in gender-affirming care is currently not part of standard medical education curricula,” said study coauthor Alex Keuroghlian, MD, MPH, director of the National LGBTQIA+ Health Education Center at the Fenway Institute and associate professor of psychiatry at Harvard Medical School, Boston, in an interview.
The study has limitations. The survey population doesn’t include anyone who committed suicide, nor does it include people who had gender dysphoria as children but didn’t go on to identify as transgender as adults. It is also retrospective. “There is a general consensus that, given the data we have so far, it would be unethical to conduct a randomized controlled trial in this space,” said study lead author Dr. Turban.
Several critics of hormone therapy in teens support a psychotherapy-based approach to gender dysphoria that considers whether other factors are at play than transgender orientation. They’ve united to attack research based on the 2015 transgender survey. In a 2021 report in Archives of Sexual Behavior, they called it “a highly skewed sample” and objected to “a conflation of ethical nonaffirmative psychotherapy with conversion therapy.”
In an interview, one of the critics – developmental psychologist and retired University of Sydney professor Dianna Kenny, PhD – said the new study’s “serious problem of recall bias” about hormone therapy in the survey is “insurmountable.” The survey, she said, also fails to explore why participants who wanted hormone therapy didn’t get it.
Dr. Kenny, who believes all hormone therapy in teens with gender dysphoria outside of clinical trials is inappropriate, also pointed out that hormone therapy has many side effects. She added that young people with gender dysphoria often “realize through a process of cognitive and psychosocial maturation that they were not ‘genuinely’ trans but suffering from other conditions that needed treatment – e.g., internalized homophobia, trauma, including sexual abuse, attention-deficit/hyperactivity disorder, autism spectrum disorder, etc.”
No specific funding is reported, although two of the authors report receiving various grants, fellowship and research funding. Dr. Turban discloses textbook royalties from Springer Nature and expert witness payments from the ACLU. Dr. Keuroghlian discloses textbook royalties from McGraw Hill. Dr. Kenny reports no disclosures.
FROM PLOS ONE